Hwee Ming Cheng
Physiology Question-Based Learning
Cardio, Respiratory and Renal Systems
Hwee Ming Cheng
Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
ISBN 978-3-319-12789-7 e-ISBN 978-3-319-12790-3
DOI 10.1007/978-3-319-12790-3
Springer Cham Heidelberg New York Dordrecht London
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Preface
“…Teacher, you have spoken well..they no longer dared to ask him any
question” Luke the Physician (20:39,40)
This book is a first fruit publication of more than a decade of organizing and
hosting in Kuala Lumpur, Malaysia the Inter-Med School Physiology Quiz
(IMSPQ). This is now a mega physiology event and at the recent 12th IMSPQ,
2014, we gathered 88 medical school teams from 23 countries who came
converge for a 2 day adrenaline-high, physiologically stimulating activities.
Physiology questions asked in the competition is the focus of the IMSPQ.
Above the friendly tussle for the Challenge Trophy (named in honor of Prof A
Raman, the first Malaysian professor of physiology at the University of Malaya),
the IMSPQ event is a nucleus for learning and enjoying physiology. The IMSPQ
is an invaluable test experience where students of physiology from diverse
curriculums of numerous countries are evaluated in the same sitting.
Valuable insights have been gained from a study of the common incorrect
responses to the physiology questions asked during both the silent, written and
the oral quiz session before a live audience. This book distills some of the major
physiological concepts and principles that are part of the IMSPQ challenge.
Three systems, cardiovascular, respiratory, and renal are covered, including
integrated topics that synthesize essential homeostatic mechanisms of interorgan
physiology.
This book is not purposed merely for preparations for teams gearing up for
an IMSPQ event. The questions and explanations given, will be a resource for
understanding physiology as they highlight the framework and major pillars of
physiological knowledge in each system. These questions will provide a good
foundation for students to build upon as they continue to pursue the wonders of
human physiology.
My appreciation to Thijs van Vlijmen, who from our first meeting,
recognized the usefulness of harvesting the IMSPQ for a fruitful book and was
enthusiastic in producing this Physiology Question-Based Learning (Pq-BL)
series. My student Adlina Athilah Abdullah drew the beautiful flower-blooming
heart, lungs, and kidneys (and other illustrations in the text) that introduce the
three branches of this PqBL.
At the 12th iMSPQ, we had more than a hundred physiology educators that
accompanied their student teams. I hope this book will also be a good teaching
tool for lecturers in all their educational efforts to communicate physiology well.
Dr Cheng Hwee Ming Department of Physiology, Faculty of Medicine,
University of Malaya, Kuala Lumpur, Malaysia
University of Malaya, Kuala Lumpur, Malaysia
chenghm@ummc.edu.my
Physiological Flows
I use the hot iron as a painting tool. Movements manipulated by the iron (on
which wax paints are applied) are like brushstrokes, for example, shifting and
lifting the iron creates wave-like or capillary-like forms. To me, a single
movement of the iron signifies a moment in time. It is that single moment, the
‘here and now’ that holds all reality. With this way of thinking, making an
artwork is a very direct, focused, yet intuitive activity . Chew Lean Im
This creative piece by my college friend, Lean Im reminds me of the
importance of flow in physiology, including blood flow, airflow, and urine flow.
Cheng Hwee Ming
The Questioner and the Questioned (Not the Alligator
Interrogator and the Chicken!)
There is much value in using carefully designed questions in teaching. Learning
physiology can be improved by the use of well-constructed questions. There are
three situational types of question dynamics we can consider: the teacher
himself, the teacher–student relationship, and the student learning community.
Teacher as questioner, to himself: self-conversation
a. Why does she misunderstand this mechanism?
b. How can I make her think through this mechanism physiologically?
c. What are the main concepts to convey to my students?
d. What foundational knowledge does she need before she can proceed to
understand this mechanism? ( Physiolego knowledge blocks)
e. How can I reduce mere “swallowing of information” and promote more
chewing and thinking through the physiology?
Teacher as questioner to student (Homeostatic teaching)
1. To uncover misperceptions
2. To highlight inaccurate thinking process
2. To highlight inaccurate thinking process
3. To stimulate curiosity
4. To strengthen the conceptual learning
5. To guide into integrative thinking on whole body physiology
6. To entrain the ability to apply physiology to pathophysiology
Student to student, peer teaching and “self-directed” learning
The teacher by his planned questioning, model for his students how to think
through and enjoy learning physiology among, and by themselves.
Contents
Part I Cardiovascular Physiology Introduction: Cardiovascular Physiology
1 Ins and Outs of the Cardiac Chambers
2 Cardiac Cycle
3 Blood Pressure
4 Systemic Circulation and Microcirculation
5 Regional Local Flow Regulation
Part II Respiratory Physiology Introduction: Take a Slow, Deep Breath and
Inspire the Concepts
6 Airflow
7 Upright Lung, Ventilation, and Blood Flow
8 Oxygen Respiratory Physiology
9 CO 2 Respiratory Physiology
10 Respiratory Control
Part III Renal Physiology Introduction: Renal Physiology
11 Renal Hemodynamics and GFR
12 Tubular Function
13 Potassium and Calcium Balance
14 Water Balance
15 Sodium Balance
Part IV Cardio-Respi-Renal Physiology Blessed are the Integrated, a
Physiologic Sermon on the Mount
16 Cardiorespiratory Physiology
17 Cardiorenal Physiology
18 Respi-Renal Physiology
Bibliography
Part I
Cardiovascular Physiology
© Springer International Publishing Switzerland 2015
Hwee Ming Cheng, Physiology Question-Based Learning, DOI 10.1007/978-3-319-12790-3_1
1. Ins and Outs of the Cardiac Chambers
Hwee Ming Cheng1
(1) Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
Hwee Ming Cheng Email: chenghm@ummc.edu.my
The flow of blood through the normal, healthy heart is always unidirectional, in
both the right and left sides of the heart. This is endured by the sequential,
opening and closing of the atrioventricular valves and the aortic/pulmonary
valves. Blood flows when there is a pressure gradient. The phasic changes in
atrial and ventricular pressure during a cardiac cycle determine, in concert with
gating valves, the unidirectional intracardiac flow. The student should
understand what generates the pressure that ejects blood volume from each
ventricle and what pressure gradient drives the inflow or ventricular infilling of
blood during diastolic relaxation phase of the cardiac cycle. The questions below
address the physiology of some of these cardiac events.
1. What cardiac index is used as a quantitative measure of myocardial
contraction strength?
Answer
Myocardial contractility is the term for the power of cardiac muscle contraction
and is represented by the ejection fraction.
Concept
Cardiac muscle contract as for skeletal muscles. Both muscle types perform
work, the skeletal muscles in isotonic contraction and the heart does cardiac
work in ensuring a continuous blood perfusion to all the peripheral tissues. The
strength of cardiac muscle contraction can also be increased. In the skeletal
muscles, graded muscle tension is increased by recruitment of more motor units
and higher frequency of motor nerve impulses to produce summative, titanic
and higher frequency of motor nerve impulses to produce summative, titanic
contraction.
In cardiac muscles, the strength is increased by cardiac sympathetic nerve
and circulating hormones, the main one being adrenaline, that binds to beta
adrenergic receptors on the cardiac muscles, that are also activated by
neurotransmitter noradrenaline released from the sympathetic fibers.
The increased contractility is also represented by the increased ejection
fraction. The ejection fraction is the ratio of the ejected stroke volume and the
end-diastolic volume (EDV) in the ventricle before contraction. For a given
EDV, more volume is pumped out by the more contractile ventricle. The volume
remaining in the ventricle after systolic contraction, the end-systolic volume will
be reduced when myocardial contractility is increased.
In hyperthyroidism, the contractility is also increased by the excess
circulating thyroid hormones. Thyroid hormones upregulate beta adrenergic
receptors on the cardiac muscle and potentiates the sympathetic/adrenaline
positive inotropic actions. Positive inotropism means the same as increased
myocardial contractility/higher ejection fraction. Thyroid hormones can also
alter the myosin ATPase type in the cardiac muscle, which also accounts for the
greater contractility.
2. In Starling’s mechanism of the heart, what are the y- and x-axes of the
Starling’s graph?
Answer
The x-axis is the EDV and the y-axis is the stroke volume.
Concept
The mechanical property of the cardiac ventricle muscles described by Starling
is an intrinsic muscle phenomenon. By “intrinsic” this means that no extrinsic
nerve or circulating hormones play a role in the Starling’s mechanism (or Law)
of the heart.
The heart is a generous organ. If it receives more blood volume, it will give
out more blood volume. The heart does not hoard! Using cardiac volumes to
describe Starling’s event, this states that the greater the physiologic increase in
the EDV, the bigger will be the stroke volume.
The axes of the graph can also represent x-axis as ventricular filling (venous
return) and y-axis as cardiac output. A larger EDV stretches the ventricular
muscle and the contracting tension is greater. The histophysiologic basis for this
is the degree of potential overlap between the actin and myosin filaments in the
cardiac muscle at different lengths.
Up to an optimal length, the increase in EDV and hence cardiac muscle
Up to an optimal length, the increase in EDV and hence cardiac muscle
length will be followed by a larger ejected, stroke volume.
Note that the ejection fraction is unchanged (this fraction is a measure of
myocardial contractility, question 1 above).
This “more in more out” ventricular Starling’s mechanics applies in both the
left and right ventricles. The maximum systolic intraventricular pressure is much
higher in the left ventricle (120 mmHg) compared to that in the right ventricle
(~ 30 mmHg). However, the stroke volume (SV) of each ventricle is the same,
because the cardiac work has to be higher for the left ventricle against a higher
“afterload” (~ 100 mmHg) than the afterload at the right side represented by the
mean pulmonary arterial pressure.
The intraventricular and aortic/pulmonary vascular pressures are different on
each side of the heart, but the volume dynamics (EDV and SV) of the Starling’s
cardiac mechanism is the same and operative in both ventricles.
The ejected blood volume with each heartbeat (stroke volume, SV) is determined by two contributing
factors. One is an intrinsic cardiac muscle mechanism (Starling’s law) where SV is dependent on
ventricular filling (EDV). The other way to increase SV is by an increased cardiac sympathetic nerve action
or by higher circulating adrenaline that both produce a greater myocardial contractility. Increased
contractility is defined by a bigger ejection fraction (SV/EDV)
3. What mechanism ensures that the right and left ventricular cardiac outputs are
equalized over time?
Answer
Starling’s mechanism of the heart has the essential physiologic role in
equalization the cardiac output of the two ventricular pumps that are arranged in
series.
Concept
The figure in physiology texts sometime gives the students the impressions that
the systemic and the pulmonary circulations are in parallel. If we imagine
stretching out the whole circulatory system into a chain, the right and the left
ventricles would be seen to be connected in series like two beads along the
“bloody” vascular chain.
“bloody” vascular chain.
The serial arrangement of the right and left ventricular pumps present a
potential problem for the vascular blood traffic flow. It is crucial that the two
pumps are synchronized with regards to the cardiac output “put out” be each
ventricle. Should there be unequal cardiac outputs, very soon we will have
problems of vascular traffic congestion.
Beat by beat, there could be small fluctuations in the stroke volume from
each ventricle. There are 60 beats in each minute, and the differences in the
stroke volumes will accumulate to produce unequal cardiac output if there is no
mechanism to adjust for this.
This is where the intrinsic Starling’s myocardial mechanics becomes
important. If one ventricle has a larger cardiac output, this will mean a greater
filling of the other ventricle. The second ventricle then contracts more strongly.
If the second ventricle does not intrinsically pumps out more of what it has
received (increased EDV), then the traffic “upstream” from the second ventricle
will be congested.
To give a clinical illustration, if the right ventricle weakens, there will be
venous congestion (with development of peripheral edema). On the other “hand”
(“heart”), left ventricular failure will result in pulmonary venous congestion and
this can cause pulmonary edema.
“O my Starling, my heart(s) beat for you!”
4. In a transplanted heart, how may cardiac output be increased during physical
activity?
Answer
The cardiac function of the denervated transplanted heart responds to circulating
hormones.
Concept
The life-giving heart can be donated. The heart has autorhythmicity, the
sinoatrial (SA) pacemaker cells spontaneously generating action potentials that
are transmitted throughout the myocardium.
The normal heart does not require extrinsic neural innervation to maintain its
cyclical beats or contractions. The pacemaker activity is increased by
sympathetic input that produces the tachycardia during exercise. In the
transplanted heart, the SA node can still be stimulated by circulating adrenaline
from the adrenal medulla.
The sympatho-adrenal medullary axis supplements the direct sympathetic effects on the heart. The
adrenergic receptors at the sinoatrial node and the ventricular muscles bind to circulating adrenaline besides
binding the neurotransmitter noradrenaline released from cardiac sympathetic nerve terminals
Cardiac output is the product of the heart rate and the stroke volume. The
ventricle contraction of the heart can also be strengthened by adrenaline.
Adrenaline increases both the heart rate and the contractility (increased ejection
fraction) of the heart.
In the overall circulation, it is natural to view the heart as the center of all
functions. This cardiocentric concept of blood circulation physiology may hide
the important key contribution of venous return in the closed circuit of the
cardiovascular system. The heart only pumps out what blood volume fills it, and
the operating blood volume is a fixed entity.
Thus, the venous return is certainly an important provider for the increased
cardiac output during physical activity in a person with a donor’s heart. Venous
return is increased during exercise by several factors including muscle pump
effect and respiratory pump effect of central venous pressure. Sympathetic
venoconstriction also decreases the venous capacitance, so more blood is
available to circulate.
The sympathetic nerve activates the beta receptors (beta looks like a standing heart!) on the sinoatrial node
and the ventricular muscles to produce tachycardia and increased myocardial contractility that ejects a
larger stroke volume. The sympathetic neurotransmitter is noradrenaline. Secretion of the adrenal medullary
catecholamine, adrenaline is also stimulated by sympathetic cholinergic nerve. Adrenaline binds and acts on
the cardiac beta receptors
5. What ensures that the atrial and ventricular contractions are orderly and
sequential?
Answer
The slight transmission delay at the atrioventricular node allows the ventricular
systole to proceed only after the artila systole.
Concept
The left and right ventricles contract simultaneously. The ventricles function
together like a syncytium. The right and left atria also contract as a functional
syncytium. The cardiomyocytes in both the ventricles and the atria are
electrically coupled via gap junctions, besides being spread of the action
potentials by the conducting fibers.
Atrial systole occurs during the final stage of ventricular diastole when the
ventricles are filled with blood. The EDV is achieved by both passive ventricular
infilling of blood and a “top-up” by atrial contraction.
If is thus imperative that the ventricles are not depolarized too soon after
atrial depolarization. This will allow the atrial systole to fill the ventricles before
the ventricles contract.
The transmission of impulses from the sino atrial pacemaker through the
atrial muscle is slightly slowed at the atrioventricular node, the only transit
electrical point between the atria and the ventricles. The atrioventricular “delay”
ensures that atria depolarization and generation of action potentials are near
completed before the ventricles become depolarized (the “P” wave is temporally
separated from the “QRS” complex).
6. How does the function of the cardiac/vascular valves signal the different
phases of the cardiac cycle?
Answer
Closure of atrioventricular valve begins the systolic phase of the cardiac cycle
and closure of the pulmonary/aortic valves signal the start of diastole.
Concept
The cardiac cycle of the rhythmic beating heart is divided into the ventricular
filling phase during diastolic relaxation and ventricular systolic contraction
phase. The cardiac valves ensure that the intracardiac flow of blood is
phase. The cardiac valves ensure that the intracardiac flow of blood is
unidirectional, only from the atria into the ventricles.
When the ventricular muscles are depolarized, the mechanical contraction
develops. As the ventricular muscle tension starts to increase, very soon the
intraventricular pressure exceeds the atrial pressure. The mitral and tricuspid
valves at the left and right side of the heart, respectively, snap shut. This
produces the first heart sound. This begins the systole and the initial brief period
of systole is an isovolumetric contraction when the intraventricular pressures
build up steeply until the point when the pulmonary/aortic valves are forced
open during the ejection phase.
When the ventricles are repolarized, this will relax the muscles. When the
intraventricular pressures drop to less than the pulmonary/aortic arterial
pressures, the pulmonary/aortic valves shut. This produces the second heart
sound. Backflow of the pulmonary and aortic blood in to the ventricles is
prevented.
The closure of the these valves begins the diastole, and the initial period of
diastole is the isovolumetric relaxation when the intraventricular pressure drops
precipitously until the tricuspid and mitral valves open for ventricular filling.
When the cardiac or vascular valves do not close completely, this is termed a
valvular insufficiency. An insufficiently shut valve will result in a heart murmur.
For example, if the left mitral valve is insufficient, contraction of the left
ventricle will squirt blood flow abnormally back into the atria. A systolic
murmur is heard during the first heart sound.
If the aortic valve is insufficient, the back flow of blood into the left
ventricles during diastole occurs. A diastolic murmur is heard at the second heart
sound.
On the normal electrocardiogram (ECG), it would benefit the student to
attempt to reason and derive that the first heart sound is located just after the
QRS ventricular depolarization wave, and the second heart sound is placed just
after the T-ventricular repolarization deflection.
7. What are the two pressures that determine the ventricular filling of blood from
the systemic circulation?
Answer
Venous return is driven by the perfusion pressure which is the difference of the
mean circulatory (systemic) filling pressure and the right atrial pressure (rap).
Concept
The rap is functionally synonymous with the central venous pressure. The mean
systemic filling of circulatory pressure (msfp) is the average pressure in the
systemic filling of circulatory pressure (msfp) is the average pressure in the
systemic circulation that determines the venous return. Experimentally, the msfp
is obtained by acutely stopping the heart of the animal from beating. The rap is
then measured. Since the cardiac output is now zero, the average pressure in the
systemic circulation and the rap must be the same. This is what is conceptually
called the msfp.
From the basic hemodynamics equation, the flow is equal to the perfusion
pressure/vascular resistance. When we consider venous return, this will translate
to Venous return = msfp minus rap/venous return.
Since venous resistance is small in contrast with arterial resistance, venous
return is basically conditioned by the msfp and rap.
To illustrate with clinical situations, right ventricular failure will raise the
central venous pressure. Venous return is impeded and venovascular congestion
develops. Hypovolemia from any causes decreases the msfp resulting in
reduction of venous return and cardiac output.
Doing a Valsalva maneuver (e.g., include straining at stools, exertion during
labor) increases the intrathoraic and central venous pressure. The perfusion
pressure to deliver venous return becomes smaller. A similar situation of
increased central venous pressure would be in patients maintained on positive
pressure breathing.
During exercise, the venous return is enhanced, since deeper tidal volume
breathing decreases the rap. This is described as a “respiratory pump” effect.
This Chinese pictogram of “heart” resembles the cardiac ventricles. The extreme left stroke would then
represent physiologically the venous return and the far right stroke the cardiac output. In a closed
circulatory system, the venous return would equal the pulmonary blood flow (right cardiac output) and the
rate of ejected blood flow from the left ventricle into the systemic circulation
8. Is there a proportionate relationship between heart rate and cardiac output?
Answer
At high tachycardia, the decreased diastolic filling time tends to reduce stroke
volume, and so the cardiac output does not increase linearly with increase in
frequency of heart beat.
Concept
The heart pumps out only what it contains. The volume of blood pumped out per
beat (stroke volume) is determined by both the EDV and the myocardial
contractility (increased by sympathetic nerve/adrenaline).
The diastolic period is more significantly reduced than systole during
tachycardia when the cardiac cycle is shortened. This has the effect of reducing
the EDV.
We can then expect that since the cardiac output is the product of heart rate
and stroke volume, the cardiac output will not increase proportionately with
increasing frequency of heart beats.
The student should not mix up the effect of heart rate on stroke volume and
the cardiac output. The stroke volume could be lessened due to the reduced
ventricular filling and thus the EDV. However, the cardiac output is still more
than the value at rest.
The student should be reminded that whenever tachycardia occurs, the
cardiac sympathetic nerve is stimulated (concurrent with a decreased vagal
parasympathetic activity to the pacemaker cells).
This means that the sympathetic tachycardia as in exercise is always
concurrent with a positive inotropic effect of sympathetic action on the
ventricular contractility (the sympathetic nerve releases adrenaline also from the
adrenal medulla). What this indicates is that although the EDV is less, the
ejection fraction is enhanced by the increased myocardial contractility. The net
effect is that the stroke volume may not be that much decreased during greater
cardiac activity. In a situation when only the tachycardic reduction of the EDV is
considered, the effect on the cardiac output will theoretically be more, if
sympathetic action on producing a higher ejection is ignored.
9. How does venous return directly influence the heart rate? Bainbridge reflex
Answer
Increased venous return produces an increased heart rate to help maintain an
optimal rap.
Concept
The rap or central venous pressure (cvp) is near 0 mmHg. This rap (cvp)
fluctuates during a normal respiratory cycle, slightly lower during inspiration
compared to expiration. The venous return graph has the rap as the x-axis and
venous return as the y-axis. The graph shows an inverse relationship between the
rap and venous infilling of the heart.
In the venous return graph, rap is the cause and venous return flow is the
affected factor. Since the circulation is a closed system, it is also true that venous
return changes as a causative factor effect and alter the rap. This venous
return/rap coupling explain the reflex response to increased venous return on
producing a tachycardia. This is also named the Bainbridge reflex.
The student who is familiar with the baroreflex will wonder at the integration
between the Baindridge and the carotid/aortic baroreflex. Any increase in venous
return would lead sequentially to an increased cardiac output and arterial blood
pressure. The typical baroreflex to the increased blood pressure is a bardycardic
response.
Thus, we have a direct tachycardic effect of increased venous return and an
indirect bradycardic effect of a higher venous return via the baroreflex
mechanism.
The text in Boron’s Medical Physiology proposed that the Bainbridge effect
is more prominent in hypervolemia in order to prevent an elevation of rap or
central venous pressure. This could potentially cause venous vascular
congestion. In hypovolemia/hypotension, the compensatory,
baroreflex/sympathetic effector action is given priority.
10. How is the hemodynamics of a rhythmic pump different in terms of flow and
pressure?
Answer
For the rhythmic cardiac pump, the flow or cardiac output is not proportionate to
the pressure as the aortic blood pressure is also the “afterload” against which the
rhythmic pump contacts.
Concept
For vascular flow, the basic hemodynamics apply where flow = perfusion
pressure/vascular resistance of that segment of the circulation. When the blood
flow of the overall systemic circulation is considered, the rhythmic nature of the
cardiac pump changes the hemodynamics.
We could still consider the left to right heart flow (cardiac output) as the
pressure difference divided by the total peripheral resistance. The pressure
difference or driving pressure would be the difference between the aortic and the
rap. We cannot use the left intraventricular pressure in the hemodynamics of
left/right heart flow as the cardiac pump is rhythmic, and intraventricular
pressure during diastole is close to 0 mmHg.
The aortic or mean arterial pressure is the “head” pressure for providing the
continuous flow to the periphery. When the ventricle contracts and pumps from
relaxed position, the ventricle has to pressurize against the aortic blood pressure
to produce blood flow. The aortic pressure represents the “afterload” (the
afterload of the right ventricle is the pulmonary arterial pressure).
In hypertension, the “left” afterload is elevated, and more cardiac work has
to be done to pump to perfuse the peripheral tissues. The chronic overload on the
left ventricle leads to ventricular hypertrophy. Likewise, in pulmonary
hypertension, the right ventricle is burdened with extracardiac work. Right
ventricular hypertrophy develops.
© Springer International Publishing Switzerland 2015
Hwee Ming Cheng, Physiology Question-Based Learning, DOI 10.1007/978-3-319-12790-3_2
2. Cardiac Cycle
Hwee Ming Cheng1
(1) Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
Hwee Ming Cheng Email: chenghm@ummc.edu.my
The rhythmic heart repeatedly pumps, relaxes to “top-up” and pumps. In a
cardiac cycle, there are two main phases, the contraction (systole) and the
relaxation of the ventricles (diastole). Although the atria also have their own
cycle of similar contractile activity, the use of the words systole and diastole
refer to the ventricles that eject blood out with each stroke volume. There are
cyclical intraventricular pressure and volume changes. The pressure/volume
changes can be matched to the electrical activity that starts at the sinoatrial
pacemaker cells and its sequential transmission and spread across the whole
myocardium (electrocardiogram, ECG). In addition, the profile of pressure
changes in the atria, ventricles, and aorta/pulmonary artery which is associated
with opening and closing of valves, the latter generating the major first and
second heart sounds. The changes in aortic blood pressure during a cardiac cycle
represent the peak systolic blood pressure and the minimum diastolic blood
pressure. Understanding the cyclical changes in these parameters takes time, to
ponder the step by step cardiac events.
The clockwise arrow direction indicates the unidirectional blood circulation through the left ventricle and
the right ventricle, both ventricles are in series, with the lungs in between. The rate blood flow from the
more muscular left ventricle (cardiac output) must be equalized with the right ventricular cardiac output to
avoid any vascular “bloody traffic” congestion
1. Why is the P wave of a normal ECG always smaller than the QRS
complex?
Answer
The amplitude of the deflections of a normal ECG is determined by the mass of
the tissue that has been depolarized/repolarized.
Concept
The ECG is a measurement of the electrical activity on the surface of the body.
The ECG tracing is not the same as action potential electrical changes of the
membrane potentials. The ECG recorded does result from the spread of action
potentials through the heart.
The heart is in a conducting medium and electrical currents generated around
the surface of the heart as it is being progressively depolarized are transmitted to
the body’s surface.
If we look at the scale of an action potential, the amplitude is ~ 100 mV. The
amplitude of the major ECG wave, the QRS complex is less than 2 mV.
The mass of cardiac muscle that is “electrified” by the spreading action
potentials will determine the size of the electrical currents generated. Therefore,
the atrial electrical activity during a cardiac cycle will produce a smaller
deflection than the larger ventricles.
Note that the smaller amplitude of the ECG “P” wave is not that the atria
contract less strongly than the ventricles. It is also not explained by the smaller
volume size of the atria.
When there is an increase in the mass of a cardiac chamber, this is then
reflected in the ECG deflection. In ventricular hypertrophy, the amplitude of the
QRS wave will be bigger.
QRS wave will be bigger.
2. How does the parasympathetic nerve affect the P–R interval and the R–R
interval?
Answer
Parasympathetic nerve acts to increase the duration of both the R–R and the P–R
intervals of the ECG.
Concept
The heart rate is spontaneously generated by the pacemaker activity of the
sinoatrial (SA) nodal cells. These action potential self-generating cells have dual
autonomic control from the parasympathetic and the sympathetic nerves.
The normal resting heart rate is due to a dominant vagal parasympathetic
input. If this vagal chronotropic tone is reduced, tachycardia occurs.
The R–R interval is one cardiac cycle, from one ventricular depolarization to
the next. A tachycardic effect will decrease the R–R interval.
From the SA node, cardiac impulses are transmitted synchronously through
the atrial functional syncytium. The cardiac impulse is slightly “delayed” at the
atrioventricular (AV) node to allow for sequential atrial and ventricular
contractions.
The AV node is the sole electrical conduction pathway from the atria to the
ventricles. In the normal ECG, the P–R interval represents the time taken for the
cardiac impulse to be transmitted from the beginning of atria depolarization to
the initiation of ventricular depolarization.
Most of the P–R interval is the time transit at the AV node.
The AV node is also innervated by parasympathetic fibers. Parasympathetic
impulses to the AV node slow the impulse transmission. The P–R interval is
lengthened.
3. Which portion of the normal ECG accounts for the long electrical refractory
period of ventricular muscle?
Answer
The prolonged depolarization of the ventricle, as thus the longer refractory
period, coincides with the ST segment of the ECG.
Concept
The cardiac ventricles have a unique electrical profile of their action potential.
There is a prolonged depolarization phase (or delayed repolarization). The
ventricular action potential has thus a plateau phase when the ventricle
ventricular action potential has thus a plateau phase when the ventricle
cardiomyocites remain depolarized.
This extended action potential also means that the electrical refractory period
of the ventricles is also prolonged. This property protects the cardiac muscle
pump from a tetanic contraction. A heart that goes into tetanic contraction will
not be filled and the essential perfusion to the brain and the heart will be cut off
during the abnormal, sustained contraction.
The QRS wave represents the depolarization event of the ventricles and the
T-deflection, the ventricular repolarization. Thus, the time period between the
de-and the beginning of the T repolarization wave is the prolonged
depolarization seen as the plateau phase of the ventricular action potential. This
is the ST segment.
By convention a “segment” of an ECG does not include a wave, while an
ECG wave is part of an “interval” period.
This ST segment is thus. When the calcium ions from the extracellular fluid
influx into the ventricular cardiomyocytes. The additional calcium cation influx
is the reason for the delayed repolarizaton of the ventricles. The entry of
extracellular fluid (ECF) calcium into the cytoplasm of the ventricular muscle
fibers triggers more calcium release from the sarcoplasmic reticulum (SR). This
ECF calcium-SR calcium trigger is described as “calcium induced calcium
release.”
4. How would you expect the increased circulating adrenaline to affect the QRS
amplitude?
Answer
Adrenaline should not alter the amplitude of the QRS complex.
Concept
The amplitude of the ECF waves is dependent on the mass of the cardiac tissue
where the electrical action potential event has occurred. The strength of cardiac
muscle contraction is not reflected in the ECG electrical profile.
Adrenaline increases both the heart rate and the myocardial contractility. The
R–R interval and the P–R interval will be shortened as the catecholamine binds
to the same beta receptors that are bound by noradrenaline released from the
cardiac sympathetic nerves.
However, the increased stroke volume due to the positive inotropic effect of
a greater cardiac ejection fraction cannot be derived from looking at the ECG. A
greater strength of contraction produced by adrenaline action does not increase
the amplitude of QRS deflection.
the amplitude of QRS deflection.
Only in case of ventricle hypertrophy and a more cardiac muscle mass does
the ECG inform us by a bigger amplitude of the QRS.
Adrenaline also does contribute to the coronary vasodilation when the heart
is more active. Increased coronary perfusion during exercise to supply the
greater metabolic demands of the cardiac muscle is not registered either by
exercise ECG.
However, the converse condition of coronary ischemia can produce some
characteristic ECG changes.
5. When does isovolumetric relaxation occur along the ECG?
Answer
Isovolumetric relaxation is the initial brief phase of ventricular diastole and
begins just after the T repolarization wave along the ECG.
Concept
The electrical event precedes the mechanical event in the heart. The first short
stage of diastole occurs when the aortic/pulmonary valves shut. The
intraventricular pressure drops markedly during this phase when all the valves
including the tricuspid/mitral valves are closed.
Diastolic ventricular filling starts when the tricuspid/mitral atrioventricular
valves open.
Ventricular diastolic relaxation occurs after the ventricles are repolarized.
Thus, diastole begins just after the T wave. Diastole will proceed until the
beginning of systole when the ventricles begin to contract and shut the
tricuspid/mitral valves. This point is just after the QRS wave. The period of
diastole during a cardiac cycle is then from the end of T wave to the end of the
QRS complex.
Thus, the systolic isovolumetric contraction begins just after the QRS
deflection and ends when the aortic/pulmonary valves are pressurized open
during ejection phase of systole.
The aortic valve opens and shuts depending on the pressure gradient between the left ventricle/aorta. When
left ventricle (LV ) exceeds the pressure in the aorta, the valve opens, and ejection of a volume of blood
(stroke volume) enters the aorta. If the aortic pressure exceeds that in the LV, the aortic valve shuts and
begins the diastole of a cardiac cycle. The LV is filled with oxygenated blood during diastolic filling with
pulmonary venous blood from the lungs
6. How does tachycardia affect the myocardial contractility? (Note the opposite
effects to no 9.)
Answer
Tachycardia has an indirect effect in increasing myocardial contractility via the
elevation of intracellular calcium in the ventricular myocytes.
Concept
When the heart is more active, it pumps more frequently (tachycardia) and more
strongly (increased ejection fraction). Both these chronotropic and inotropic
actions are effected by the cardiac sympathetic nerves and adrenaline,
respectively.
There is some additional increased cardiac contractility that results from a
higher frequency of heart beat. Each cardiac cycle of contraction is followed by
relaxation which is initiated when calcium ions are pumped by Ca-ATPase back
into the sarcoplasmic reticulum (SR) or extruded by the cell membrane Na/Ca
exchanger into the ECF.
This lowering of the cytosolic calcium precedes cardiac muscle relaxation.
With tachycardia, there is relatively less time to reduce the intracellular calcium
to resting, precontraction level.
During the next muscle depolarization event, there will be a higher
intracellular calcium when calcium from ECF influx is released from SR. The
myocardial contractility is increased proportionately to the rise in cytosolic
calcium.
Note that in skeletal muscles, graded increase in contraction strength is not
mediated by increasing intracellular calcium. Skeletal muscle tension is
mediated by increasing intracellular calcium. Skeletal muscle tension is
increased by activation of motor unit recruitment and a higher frequency of
impulses in the alpha motor neurons that innervate the muscles.
7. How does right heart failure lead to development of peripheral edema?
Answer
In right heart failure, the venous congestion leads to increased capillary
hydrostatic pressure and higher net capillary filtration that results in fluid
accumulation in the interstitium.
Concept
In a normal heart, the stroke volume (SV) is proportionately related to enddiastolic volume (EDV, preload) over a physiologic range. In the right side of
the heart, this EDV/SV pairing ensures that the central venous pressure/right
atrial pressure is consistently at a low value to maintain optimal ventricular
filling.
When the right ventricular function is compromised, the ejection volume of
the preload is not effectively pumped out. With time, venous congestion
develops with elevated central venous pressure. The increased venous pressure
will “radiate” and be transmitted into the microcirculation. This backlog of
vascular pressure easily occurs because unlike the presence of high resistance
precapillary arteriole, the postcapillary venular resistance is low.
At the capillary, the raised capillary hydrostatic pressure will disturb the
balance of Starling’s forces. The net filtration along the capillary will soon
exceed the capacity of the lymphatic drainage to maintain a low interstitial
hydrostatic pressure. Fluid accumulates in the tissue spaces (edema).
Cardiac sympathetic action increases the stroke volume directly by increasing the ejection fraction.
Indirectly, the reduced venous capacitance with sympathetic venoconstriction will also increase venous
filling that will produce a bigger stroke volume. SV stroke volume. EjF ejection fraction. VR venous return
8. How does the ventricular volume/pressure diagram illustrate the dynamic
changes during a cardiac cycle?
Answer
The ventricular x-axis volume/y-axis pressure diagram demonstrates the
beginning and ending of each of the four phases within the systole and diastole
of a cardiac cycle.
The heart is functionally two rhythmic pumps arranged in series. The contraction phase (systole) and
relaxation phase (diastole) are marked by heart sounds due to the closure of cardiac and arterial (pulmonary,
aortic) valves. Systole is the period from the first to the second heart sound, and the longer diastolic
ventricular relaxation/filling phase runs from the second to the first heart sound
Concept
The ventricular volume along the x-axis will be the same for the right and left
ventricle. However, the y-axis intraventricular pressure will be on a different
scale (maximum for left ventricle is 120 mmHg and for right ventricle is
~ 30 mmHg).
Sharp changes in pressures are clearly evident in the two vertical sides of the
volume/pressure (V/P) diagram. The diagram must also be followed
anticlockwise. This means that the right vertical line shows a steep increase in
pressure and the left vertical, a precipitious drop in ventricular pressure. These
two pressure lines at constant ventricular volumes would represent the
isovolumetric systolic contraction and isovolumetric diastolic relaxation phase.
The maximum volume in the V/P diagram is the end-diastolic volume, EDV
(~ 120 ml) and the miminum ventricular volume is the end-systolic volume
(ESV, around 40 ml). The lower horizontal line that links the two verticals is
thus the stroke volume SV (EDV–ESV). This bottom horizontal line with little
change in ventricular pressure, moving anticlockwise from ESV to EDV is the
event of ventricular filling.
The south east (SE) corner of the V/P diagram, the start of the vertical rise in
pressure is the beginning of systole. The isovolumetric contraction phase begins
when the atrioventricular valve shuts and pressure builds up rapidly before the
aortic/pulmonary valve is pressurized open. Thus, the SE is where the
mitral/tricuspid valves closes.
The upper line that extends from the upper right (NE) to the upper left (NW)
corner of the V/P diagram represents a decrease of ventricular volume from
EDV to ESV. This is the ejection phase when the ventricles pump out each of
their stroke volumes. The NE point is when the pulmonary/aortic valves are
opened.
Beginning at the NW corner of the V/P diagram, the intraventricular pressure
drops rapidly. The NW corner spot is the beginning of diastole when the
aortic/pulmonary valves shut. There is no change in volume, this initial brief
phase of diastole until the intraventricular pressure falls to below the atrial
pressure. When this is reached, tricuspid/mitral valves open (bottom, left SW
corner) and diastolic ventricular filling proceeds.
9. How is the increased myocardial contractility and Starling’s mechanism of the
heart represented by the ventricular/pressure loop diagram?
Answer
Sympathetic nerve action on the heart increases the ejection fraction and the endsystolic volume (SW corner) is shifted to the left. Starling’s intrinsic cardiac
muscle contraction mechanism is effected when the ventricular filling or enddiastolic volume (SE corner) is increased or shifted to the right.
Concept
For both cardiac sympathetic and Starling’s effects, the stroke volume is
increased. The higher SV for sympathetically—increased contractility results in
less volume (ESV) remaining in the ventricle, although the precontraction EDV
is not changed.
For the Starling’s effect, the greater stroke volume is due to a bigger volume
that fills the ventricle before contraction (higher EDV), stretching the ventricle
to a greater systolic muscle tension. The ESV is not altered by Starling’s. The
increased preload or EDV produce the larger stroke volume.
increased preload or EDV produce the larger stroke volume.
In the situation when the aortic pressure is elevated (afterload), how would
the ventricular volume/pressure loop look like? In chronic hypertension, the left
ventricle has to generate additional cardiac work force to pump the same stroke
volume against the raised afterload. For a given EDV, if the ventricle begins to
weaken, the SV will decrease and the remaining ESV will be more, shifted to the
right.
The vertical rise in pressure during the isovolumetric contraction phase of
systole (right vertical of V/P loop) will also be greater (contraction against a
higher afterload) before the aortic valve opens for the ejection of stroke volume.
10. Why does the venous return curve have the same x-axis as the cardiac output
curve, drawn on the same graph?
Answer
The venous return (y-axis) is quite obviously related to the x-axis right atrial
pressure (rap). Venous return as a primary cause proportionately affects the rap,
and thus the expected x-axis venous return for the cardiac output (y-axis) curve
can be harmonized by using the rap as the x-axis also.
Concept
The circulatory system is a closed circuit. Conceptually, the cause and effect in a
particular cardiovascular event can quite often by puzzling and confusing to the
students. The cardiac output or cardiac function curve relates the venous return
(x-axis) to the cardiac output. This is basically describing the intrinsic Starling’s
mechanism of the heart, where the ventricular stroke volume proportionately
changes with the EDV.
In the presence of cardiac sympathetic activity, the cardiac function curve is
shifted to the left; an indication that for the same EDV a positive inotropic effect
of sympathetic stimulation gives a bigger stroke volume.
What is the rationale for substituting the x-axis venous return with right atrial
pressure?
The students would have heard that changes in the right atrial pressure
(central venous pressure), as a cause, would be expected to cause an inverse
effect on venous return since the driving pressure for blood entry into the heart
would have been reduced (the inverse relationship is seen in the venous return
curve).
Because the circulatory system is a closed flow system, it is also true that if
we consider venous return as the cause, then the right atrial pressure would
change proportionately with the magnitude of the venous return. The Bainbridge
effect of increased venous return producing a reflex tachycardia is due to the
effect of increased venous return producing a reflex tachycardia is due to the
increased right atrial pressure.
The combined cardiac function and venous return (or vascular function)
curves intersect at a certain right atrial pressure. In the closed circulatory system,
this equilibrium rap is thus a net value from the dynamics of inflow venous
return and outflow cardiac output.
When we consider the cardiac output, functionally, a normal ventricular
pumping maintains an optimal rap (we have just discussed above the reverse
interactions that the rap affects cardiac output). In right/left ventricular failure,
the right/left atrial pressure begins soon to be elevated.
© Springer International Publishing Switzerland 2015
Hwee Ming Cheng, Physiology Question-Based Learning, DOI 10.1007/978-3-319-12790-3_3
3. Blood Pressure
Hwee Ming Cheng1
(1) Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
Hwee Ming Cheng Email: chenghm@ummc.edu.my
Remember the Giraffe when you think of blood pressure regulation!
Gravitational force affects the hydrostatic pressure of blood and the long-neck
animal certainly must ensure a constant adequate arterial blood pressure for its
cerebral circulation, as it walks around feeding on leaves on high trees.
1. Are the location of the arterial baroreceptors important or can the
receptors be located elsewhere e.g. in the abdomen?
Answer
The location of the carotid and aortic baroreceptors are not irrelevant to their
essential functions. Arterial baroreceptors monitor blood pressure and ensure
that blood perfusion especially to the brain is adequate. For humans that spend a
considerable of their daily activity in the upright position, the maintenance of a
normal optimal blood pressure fulfils the role of protecting the brain from
cerebral ischemia.
The location of the carotid/aortic mechanoreceptors above the level of the heart
allows the baroreceptors to detect the initial drop in blood pressure when a
person stands up from the horizontal resting position. The hydrostatic blood
pressure decreases above the heart’s level due to gravitational force. If the
baroreceptors are located below the heart’s level, they will not sense the initial
reduction in blood pressure that is a consequence of venous pooling which
lowers the stroke volume.
The carotid/aortic baroreceptors are in the high-pressure arterial side of the
circulation. They are also called high-pressure volume sensors. This is to
circulation. They are also called high-pressure volume sensors. This is to
distinguish the baroreceptors from volume sensors in the low-pressure, venous
side of the systemic vascular circuit. These volume receptors are located in the
atrial cardiac chamber and the pulmonary vasculature. They function to monitor
the “fullness” of the circulation. The afferent impulses from the volume
receptors are, like the impulses from the baroreceptors, sent to the brain stem
cardiovascular regulatory neurons.
Afferent impulses from both baroreceptors and volume receptors also input
into the hypothalamus to affect antidiuretic hormone (ADH) secretion and thirst
sensation. This is part of the water balance control.
In extracellular fluid (ECF) volume expansion, the hypervolemia stretches
the volume receptors in the atria and this releases natriuretic hormone to increase
sodium and water excretion. Changes in blood volume (determined by total body
sodium or sodium balance) will bring corresponding change in the blood
pressure via the cardiac output factor.
2. Which determinant of the blood pressure equation does venoconstriction ‐
affect?
Answer
Venoconstriction by sympathetic nerve increases venous return and this gives a
higher cardiac output since a bigger stroke volume will be produced from a
larger end-diastolic volume.
Concept
Vasoconstriction as a general term means both constriction of the arterial and the
venous blood vessels. To understand the differential vascular functions of
arteries and veins, it is useful to specify vasoconstriction when thinking about
arteriolar increased resistance which primarily determines the total peripheral
resistance (TPR).
The term venoconstriction has a different meaning as the venous effect is not so
much the contribution to TPR, but the reduction in the venous “blood reservoir”.
At rest, if you snap a photograph of the whole cardiovascular system, more than
60 % of the total blood volume is in the veins. The veins are supplied by
sympathetic nerves and the venoconstriction decreases the venous capacitance.
More blood is made available to circulate and fills the heart. A greater cardiac
output is pumped by the heart.
Rhythmic muscle contraction during physical activity like walking, jogging
also compresses the veins and increases the flow of venous blood via the inferior
vena cava into the heart.
The value of systolic blood pressure (SBP) depends on the stroke volume (SV) and the arterial compliance.
A bigger SV gives higher SBP for a given arterial compliance. Similarly for a given SV, a decreased arterial
compliance will produce a higher SBP. The diastolic BP is due to arterial recoil. A higher SV will be
accompanied by more elastic recoil. A reduced arterial compliance will lower the diastolic blood pressure
(DBP)
3. How is sodium balance and arterial blood pressure physiologically
connected?
Answer
Sodium balance essentially affects the ECF and blood volume and blood volume
is a determinant of arterial blood pressure.
Concept
There is quite a lot of popular reports and health advice that too much salt intake
is not good and predispose the person to developing hypertension. The
association and any cellular mechanisms that link the electrolyte to blood
pressure is still being studied and there may be individual salt-sensitivity in
hypertensive-prone persons.
Blood pressure is determined by both the cardiac output and the peripheral
arterial resistance. There may be vascular responsiveness that is modulated by
salt.
Blood volume as part of ECF volume is determined by the sodium balance or
the total body sodium. Changes in blood volume affect the mean systemic filling
(circulatory) pressure. This value is less than 10 mmHg (students should not
confuse this similar sounding term to systemic arterial blood pressure which is
~ 100 mmHg).
The mean systemic filing pressure is the overall, average driving perfusion
pressure for the venous return, since the central venous/right atrial pressure is
about 0 mmHg.
Control of blood pressure involving regulation of blood volume is described
Control of blood pressure involving regulation of blood volume is described
as “long-term” blood pressure control. Characteristically, blood volume
homeostasis involves several anti-natriuretic (e.g., aldosterone) and natriuretic
hormones. Actions of hormones require more time compared to rapid, neural
reflex actions. “Short-term” blood pressure control is mediated by the
baroreflex/brainstem/autonomic sympathetic effector feedback pathways.
4. How are blood pressure, ECF volume, and effective circulatory volume
(EfCV) related?
Answer
In a normal person, any increase in ECF volume will also increase the EfCV,
and this will raise the blood pressure.
Concept
The EfCV is a concept and is not a measurable entity or blood parameter.
Simply it refers to the blood volume that is effectively perfusing the tissues.
Blood must flow for the blood to have any physiologic benefit or meaning to the
cells.
Stagnant or sluggish blood flow will insufficiently meet the energy demand of
the cells and tissue ischemia results.
In a normal person, the blood volume and the EfCV are functionally the
same when the cardiac function is normal. However, if there is cardiac
dysfunction, the heart has pump failure and the cardiac output is reduced.
Therefore, although the blood volume in the person with cardiac failure is
normal, her EfCV is decreased. Her tissues will experience stagnant hypoxia.
When we consider blood volume sensing, a more specific parameter that is
monitored should rightly be the EfCV. To explain, in the above patient, the
blood volume is normal (euvolemia), but the volume/pressure receptors detect a
drop in the EfCV.
This, for example, is sensed by the intrarenal baroreceptors at the afferent
arteriole. This reflexly releases renin from the arteriolar granular juxtaglomerular
(JG) cells. The plasma renin then activates sodium-conservating mechanisms
and water retention follows. The pathophysiologic outcome is an expanded ECF
and blood volume.
In this isotonic expansion in the cardiac patient, the enlarged ECF does not
help to compensate for the decreased EfCV. The cardiac output is still poor and
activation of renin secretion will proceed, since renal baroreceptors still sense
the reduced EfCV.
Blood volume determines the blood pressure. Increased blood volume in normal adults will give a more
effective circulatory volume to the peripheral tissues. Increased blood volume will increase the venous
return by raising the mean systemic (circulatory) filling pressure
5. How does a Valsalva maneuver check for normal function of
baroreceptors?
Answer
The increased intrathoracic pressure during a Valsalva leads to decreased blood
pressure which will trigger the expected baroreflex tachycardic compensatory
response.
Concept
The forced expiration against a closed glottis during a Valsalva effort will
increase the intrathoracic pressure. This has the effect in elevating the central
venous pressure and will reduce the venous return. An acute drop in blood
pressure due to a decreased cardiac output will activate the baroreflex. The
baroreflex will increase the sympathetic discharge.
The increased sympathetic activity serves to restore the blood pressure by
attempting to increase the cardiac output as well as the TPR. A tachycardia is
thus observed when the Valsalva maneuver is sustained, demonstrating a normal
baroreceptor response.
When the person lets go and abandons the Valvalsa effort, a sudden return of
the central venous pressure to normal causes a rebound increase in the venous
return. Arterial blood pressure rapidly rises at that point. This time, the
baroreceptor will detect the increased vascular pressure stretch and a feedback
bradycardia is produced as a result of concurrent reflex increased
parasympathetic/decreased sympathetic inputs to the sinoatrial pacemaker node.
The vascular arterioles function in modulating total peripheral resistance in blood pressure control as well in
as local regional flow regulation. Noradrenergic vasoconstrictor sympathetic fibers innervate the arterioles
and determine the degree of vascular resistance. The anterior pituitary, under hypothalamic control,
regulates adrenal cortisol secretion and this steroid hormone is needed for normal vascular smooth muscle ‐
responsiveness to vasoactive agents
6. How does the renal sympathetic nerve (RSN) help to restore blood volume
after blood donation?
Answer
The action of the RSN conserves total body sodium by decreasing filtered
sodium load and increasing renal reabsorption of sodium.
Concept
The action of the RSN always decreases urinary sodium excretion. Sympathetic
is “sympathetic” to sodium balance.
Hypovolemia triggers a baroreflex increase in sympathetic nerve effector
actions. This includes the renal sympathetic arm of the autonomic neural
activity. Physiologically, the increased RSN action must restore blood volume.
The RSN effects the volume control by its effect in conserving sodium or
reducing urinary excretion of sodium. This is accomplished, because the RSN
reduces the filtered sodium load. At the same time, the RSN’s action in the
kidneys results in more sodium reabsorption.
The filtered load effect is through decreasing glomerular filtration rate (GFR)
due to sympathetic vasoconstriction of the renal arterioles.
The heightened sodium reabsorption is due to a direct action of sympathetic
fibers that innervate the proximal tubular epithelial cells. This segment of the
nephron normally reabsorbs ~ 70 % of the filtered sodium load.
The granular JG cells that secrete renin are innervated by RSN. Thus, the
sympathetic increase in plasma renin will result in active pathways that reabsorb
sympathetic increase in plasma renin will result in active pathways that reabsorb
sodium. Sodium is recovered more from the tubular fluid by actions of both
angiotensin II and aldosterone.
7. How does angiotensin II affect the two determinants of blood pressure
equation?
Answer
Angiotensin II (AII) stimulates aldosterone secretion from the adrenal glands.
AII is also a strong vasoconstrictor that increases the TPR.
Concept
Angiotensin II is a multitasker in the physiologic control of blood pressure. As a
potent vasoconstrictor, angiotensin II (AII) raises the TPR in the blood pressure
equation (BP = cardiac output (CO) × TPR).
Like the sympathetic activity, this vasoconstricting action of AII would be
selective to make physiologic sense. In essential organs like the brain and the
heart, we can expect AII not to be active in increasing the vascular resistance.
In the kidneys, AII acts to complement renal sympathetic action on the
afferent/efferent arterioles. This action temporally reduces the renal blood flow
(RBF)/GFR, and this decreases the filtered sodium load. In
hypovolemic/hypotensive situations, AII has the effect of reducing sodium
excretion in the overall scheme of volume control.
Excreted sodium = filtered sodium minus reabsorbed sodium.
AII increases the renal sodium reabsorption directly by stimulating the
function of the proximal tubular cell. Of course, AII is one of the primary stimuli
(the other is hyperkalemia) for the release of aldosterone from the adrenal
cortex.
Thus, the action of AII not only increases the TPR, but AII is also a key
steroid hormone that helps to maintain ECF/blood volume. This latter parameter
is a positive factor of cardiac output.
A few other actions of AII also relates to restoring volume during fluid loss.
AII stimulates vasopressin secretion from the posterior pituitary and AII is also a
dipsogenic.
8. Why does the diastolic blood pressure (DBP) change less than the systolic
during exercise?
Answer
The decrease in the TPR during exercise consequent from vasodilation in the
muscles and the skin tend to minimize the diastolic pressure.
Concept
The systolic pressure is determined by two main factors, the stroke volume and
the arterial compliance. The diastolic pressure is due to the elastic recoil of the
aorta and large arteries, and this provides the driving pressure for continuous
blood flow during ventricular relaxation. A major factor that affects the DBP is
the TPR (imagine DBP as the elastic recoil of an inflated balloon and the outlet
the TPR; if the outlet is more restricted the balloon DBP is higher and vice
versa).
During physical activity, an extensive vasodilation in the skeletal muscles has
the effect in lowering the TPR. In addition, the need to maintain body
temperature by losing heat during exercise is effected by cutaneous vasodilation.
The overall TPR is thus reduced. Selective sympathetic constriction in the
splanchnic and the renal vasculature helps to maintain an adequate blood
pressure to power the greater tissue perfusion to the muscles.
The cardiac sympathetic activity to the heart increases the cardiac output,
which also sustains a higher blood pressure in spite of the decreased TPR during
exercise.
For a given increased stroke volume, the systolic pressure would be higher.
So should the elastic recoil pressure (DBP) from the greater stretch of the aorta
by a bigger ejected blood volume. However, the decreased TPR lessens the
effect on the DBP by the increased stroke volume.
9. How does the change in capillary blood pressure during blood loss help to
compensate for the vascular volume contraction?
Answer
Transcapillary shift of fluid from the interstitium into the capillary compensates
for the vascular volume contraction as the decreased capillary hydrostatic
pressure reduces filtration and tends towards capillary reabsorption.
Concept
In the classical capillary described in physiology texts, the net filtration of fluid
occurs at the arteriolar end and net reabsorption of fluid at the venular end (the
student should note that in some organs, reabsorption takes place along the
capillary, e.g., intestines). About 90 % of the filtrate at the microcirculation is
reabsorbed, the remaining 10 % recycled by lymphatic drainage in to the
systemic circulation.
The capillary dynamics above is dependent on the balance of Starling forces
The capillary dynamics above is dependent on the balance of Starling forces
along the capillary and in the interstitium.
During hypovolemia, the baroreflex increase in sympathetic activity
increases the arteriolar resistance in many organs including in the skeletal
muscles. “Downstream” from the arterioles, the capillary hydrostatic pressure is
reduced. This effect on capillary hydrostatic pressure produced by sympathetic
arteriolar constriction reduces even more, the drop in capillary pressure from the
hypovolemia itself.
The balance of Starling’s capillary oncotic and decreased capillary
hydrostatic pressure will shift the balance to a net reabsorption that might occur
along the length of the capillary from arterioles to venules. (in splanchnic
capillary, the usual reabsorption is enhanced by the fall in hydrostatic pressure).
In the kidneys, the glomerular capillary filters less fluid due to the decreased
RBF/GFR when the RSN constricts the arterioles.
Thus, the transcapillary shift of fluid into the vascular compartment is one of
the diverse compensatory mechanisms for hypovolemia. This is sometimes
described as “autotransfusion” of fluid from the interstitium to the blood plasma.
10. How is the perfusion pressure for coronary blood flow affected in aortic
stenosis?
Answer
The aortic pressure that determines the coronary perfusion pressure is decreased
since the aortic pressure is “downstream” from the narrowed aortic valve.
Concept
The coronary blood supply to the ventricles is affected by the cardiac muscle
contraction. The mechanical contraction compresses the blood vessels during
systole. Thus, especially at the left ventricle where a higher muscle tension is
generated to produce a higher systolic intraventricular pressure of 120 mmHg,
considerably more blood flow occurs during diastole when the ventricle muscles
relax.
During systole, due to the aortic stenosis, the aortic blood pressure does not rise
as high during ventricular ejection. Therefore, during diastole, the “head”
pressure for perfusing the coronary vasculature is also reduced.
When the aortic valve is narrowed, the ventricular muscle tension is
heightened during pumping contraction. This also lessens the coronary blood
flow due to the greater compression on the coronary vessels.
If the aortic valve fails to close normally, there will be a back-flux of blood
into the ventricles. This will also lower the diastolic pressure in the aorta. Again,
the diastolic coronary perfusion to the ventricles is reduced.
the diastolic coronary perfusion to the ventricles is reduced.
Our heads are above our hearts for most of our human days. One key reasons for maintaining an adequate
arterial blood pressure is to ensure sufficient cerebral blood perfusion to our brains. The location of the baro
sensors at and above the heart’s level is also a creatively appropriate design, to allow the baroreceptors to
monitor a decrease in blood pressure. This blood pressure regulation will be appreciated when we next look
at a Giraffe!
© Springer International Publishing Switzerland 2015
Hwee Ming Cheng, Physiology Question-Based Learning, DOI 10.1007/978-3-319-12790-3_4
4. Systemic Circulation and
Microcirculation
Hwee Ming Cheng1
(1) Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
Hwee Ming Cheng Email: chenghm@ummc.edu.my
The microcirculation refers to the end-user point of the cardiovascular system.
This is the capillary network that supplies the cells with oxygen/nutrients and
drains away the metabolite CO2 and other byproducts of cellular activity. There
is a continuous flux and exchange of fluid and solute at the capillary. The
function of the lymphatic drainage system is also associated with the capillary
dynamics.
1. In general, what proportion of capillary filtrate is reabsorbed back into the
capillary at the venule end?
Answer
About 90 % of capillary filtrate is generally reabsorbed back at the venular end
of the capillary.
Concept
In the classical “textbook capillary” capillary filtration is shown to occur at the
arteriolar end of the capillary. Towards the exit of the capillary into the venules,
reabsorption of fluid takes place. This net filtration and net reabsorption at
different ends of the capillary is explained by the progressively decrease in
hydrostatic pressure along the capillary (from 30 mmHg to 15 mmhg). The
capillary oncotic pressure however is relatively constant along the capillary
length (~ 25 mmHg).
The other two Starling’s extracapillary interstitial forces do not change. The
interstitial oncotic pressure about 5 mmHg and the interstitial hydrostatic at zero
or even negative mmHg. Computing the four Starling’s forces indicate a positive
net filtration pressure at the arteriolar end and a negative net filtration (positive
reabsorption) near the venule.
About 90 % of the filtrate is recycled back into the capillary. The balance
10 % is returned to the systemic blood via the lymphatic drainage. There is thus
a major plasma fluid circulation in the blood vessels, powered by the contracting
heart and a minor fluid recirculation through the lymphatic system. The
lymphatic also drains some plasma proteins that leak out, so the interstitial
oncotic pressure does not build up to interfere with capillary reabsorption.
The student should note that in certain organs, the capillary dynamics are
quite different as they are adapted to the function they serve. For example, in the
intestines, reabsorption of fluid occurs along the capillary length, which is
appropriate for the high absorptive activity of the gut.
Conversely, the glomerular capillary only filters with a significant fraction of
20 % of renal plasma flow entering the Bowman’s capsule. The glomerular
oncotic pressure thus rises among the glomerulus.
In contrast, for the renal peritubular capillary which is downstream in series
from the glomerulus, reabsorption is perhaps the sole capillary event as in the
intestines.
2. What is the main determinant of blood viscosity and effective osmotic
pressure in the microcirculation? (Red blood cell (Rbc) plasma proteins)
Answer
Blood viscosity is determined predominantly by the hematocrit. The osmotic
pressure at the capillary is due to the plasma protein which is nonpenetrating at
the endothelial cells.
Concept
The blood volume is made up of the hematocrit and the plasma volume.
Hematorcrit is about 45 % in males and slightly lower in females. Blood
viscosity is a factor that contributes to the vascular resistance. Unlike the
vascular radius that can be regulated by sympathetic nerve and vasoactive agents
(and resistance is inversely related to radius4), the hematocrit is homeostatically
maintained by controlled erythropoiesis.
In polycythemia, the viscosity and thus the resistance to blood flow is
increased. Thus, the compensatory secondary polycythemia from exposure to
high altitude hypoxia has a self-limiting benefit. If the increases in blood
viscosity begin to make the flow sluggish, then the delivery of oxygenated blood
viscosity begin to make the flow sluggish, then the delivery of oxygenated blood
to the cells is still compromised.
The plasma protein concentration provides the effective osmotic pressure at
the microcirculation. The vascular space is importantly maintained by this
plasma oncotic or colloid osmotic pressure. The value is 25 mmHg, a small
value (less than 2 mOsm/L) compared to the total plasma osmotic pressure
equivalent to ~ 300 mOsm/L.
Sodium and its associated anions, however, are freely penetrating at the
capillary and do not exert an osmotic pressure to determine the fluid movement
at the microcirculation.
The plasma oncotic pressure is the essential osmoactive force that preserves
the volume of the vascular compartment.
Sodium and its anionic partners are the predominant osmoactive solutes at all
cell membranes and is the deciding factor for fluid shift between the intracellular
and extracellular spaces.
For fluid movement between the interstitium and the vasculature, the
governing “prince” is protein.
Angiotensin II is a strong vasoconstrictor and elevates blood pressure (BP) by increasing the systemic total
peripheral resistance. The glucocorticoid cortisol is needed for vascular responsiveness, a permissive action
for normal vascular sensitivity to vasoactive agents
3. How are the hemodynamic determinants of flow in a single capillary applied
to the whole systemic circulation from left to right side of the heart?
Answer
The flow is equal to the perfusion pressure over the vascular resistance in a
single capillary, but in the capillary network, the overall resistance is reduced by
the extensive parallel vascular conduits.
Concept
Concept
The hemodynamics of a blood flow in the vessel is described by the same factors
that govern fluid flow in a rigid tube. Flow = pressure difference/resistance to
fluid flow.
The resistance is inversely related to the fourth power of the radius in the
single blood vessel.
If we, then, compare one capillary with one artery, the arterial resistance
would be less if the same pressure gradient and flow rate is present at both blood
vessels.
In the body, however, the major resistance to blood flow is not at the
capillary section but at the arterioles. This is due to a number of reasons.
Firstly, the capillary network is an extensive branched microcirculation that
ensures blood perfusion to all corners of the tissues. This microcirculatory tree
lowers the overall capillary resistance to blood flow.
The arterioles are the resistance vessels in the systemic circulation. The
arteriolar smooth muscles are innervated by sympathetic vasoconstrictor nerves.
There is a basal vasoconstriction vasomotor tone that contributes to the
physiologic function of the arterioles as vascular resistance “gate control” for
blood perfusion “downstream” into the capillary microcirculation.
When we apply the flow = pressure/resistance to the entire systemic
circulation from left to right sides of the heart, the equation converts to
For the pulmonary circulation, which is in series with the systemic circuit,
the hemodynamics will be
4. How does the capillary blood-flow rate (ml/min) compare to the arterial blood
flow?
Answer
The normal capillary flow rate is the same as the arterial flow rate in the closed
circulatory system.
Concept
It is quite essential to use cardiovascular language accurately. When we ask
“how fast does the blood flow?,” we are referring to the velocity of blood flow
(unit will be distance/time). However, when we say “blood flow rate,” we should
be meaning the volume of blood per time.
In a close circulatory loop, the blood flow rate is the same at any segment of
the circulatory system of vascular traffic. The two circulations, the systemic and
the pulmonary have the same blood flow rate, i.e., the cardiac output and the
pulmonary blood flow has the same value; 5 l/min in a 70 kg, male adult.
The velocity of blood flow is inversely associated with the total cross
sectional area (CSA) of the vascular segment. The capillary network has the
highest CSA and the corresponding lowest velocity of blood flow. The high
CSA is obviously for the diffusion of solutes, respiratory gases and filtration of
fluid between the microcirculation and the cells.
The slow velocity of capillary blood flow complements the high CSA is
allowing optimal time for capillary exchange, the key function of this vascular
life-giving network.
If we examine the hemodynamics, the flow in the blood vessel as
volume/time can be expanded to CSA × length of vessel/time. This converts to
flow = CSA × Velocity. Since the flow (ml/min) is the same in every sector of
the circulation, the velocity of blood flow at each stage of the “bloody” journey
will be inversely dependent on the total CSA.
Control of sodium balance is part of the extra cellular fluid (ECF)/blood volume control and blood volume
is a major determinant of blood pressure
5. How does the hemodynamic principle explain the myogenic response at the
precapillary arteriole during hypotension?
Answer
The myogenic feedback responds by relaxing the arteriolar smooth muscle to
produce vasodilation during decreased perfusion pressure.
Concept
When blood pressure decreases, the feedback mechanisms from the baroreflex
will produce an increased in centrally mediated (brain stem cardiovascular
control neurons) sympathetic vasoconstriction.
It should be noted that this brainstem reflex will help to restore the arterial
blood pressure centrally via the baroreflex. The additional point to note in this
blood pressure centrally via the baroreflex. The additional point to note in this
increase in “total” (better word is overall) peripheral resistance does not include
and affect the blood flow to essential tissues of the heart and the brain.
Sympathetic nerve regulation of arteriolar radius is not a key feature in both
cerebral and coronary circulation.
In the heart and the brain, the intrinsic autoregulation of blood flow protects
the organs from fluctuations in blood perfusion pressure. The baroreflex
maintenance of an adequate blood pressure during hypotension is supplemented
by local vasodilation of the coronary/cerebral arterioles.
This local, flow autoregulatory response is an inherent property of the
arteriolar smooth muscle, involving either less or more calcium influx to produce
vasodilation or vasoconstriction, respectively. This is known as the “myogenic
response”.
Besides the “myogenic” mechanism, a local metabolite vasodilator feedback
is also operational during hypotension to compensate for the reduced blood flow
in the cerebral/coronary vasculatures.
Angiotensin II (Ang II)is a multitasker in blood pressure (BP) control. The mineralocorticoid Aldosterone is
stimulated to increase sodium conservation, and this decreases the excreted sodium. Increased sodium
reabsorption helps raise the blood volume, a determinant of cardiac output. The excreted sodium is also
reduced by Ang II action on renal arterioles to lower the glomerular filtration rate (GFR). Ang II also
increases the total peripheral resistance (TPR) component that factors into BP
6. How is venous pooling linked to changes in capillary dynamics? (edema) (no
arterial pooling, arteriolar resistance)
Answer
Venous pooling increases the venous pressure and the capillary hydrostatic
pressure as well.
Concept
When a person stands stationary without voluntarily moving his calf muscles,
When a person stands stationary without voluntarily moving his calf muscles,
the gravitational force will exert an increase in the hydrostatic pressure in his
blood vessels below the level of his heart.
There will be a progressive increase in both arterial and venous pressure, at
0.77 mmHg higher for every cm below heart’s level. The arterial pressure in a
large artery at the foot (105 cm below the heart) is 180 mmHg
[100 + (0.77 × 105)].
However, the gravitational effect of increased venous pressure affects the
capillary pressure more than the rise in the arterial pressure. This is because the
resistance of the precapillary arterioles is much greater than the low venular
postcapillary resistance.
The higher compliance of the veins produces the increased venous volume
during venous pooling. There is no equivalent of arterial pooling due to arterial
elasticity that opposes the stretch. The same increase in vascular transmural
pressure distends to a greater degree the more compliant veins.
This increased venous/capillary hydrostatic pressure will tend to produce a
peripheral edema of the dependent areas of the lower limbs. We may know from
experience that our ankles feel more tight and heavy when we have been sitting
long with little mobility, e.g., on a long air flight.
7. What are the two major drainage functions of lymphatics that maintain the
optimal interstitial space?
Answer
The lymphatic drainage returns both unreabsorbed capillary filtrate and plasma
proteins that leaked out of the capillaries.
Concept
The total interstitial fluid volume is three times the plasma volume. The
capillaries constantly filter plasma fluid minus the plasma proteins. There is a
local fluid recycling as most of the filtered fluid is reabsorbed downstream along
the capillary.
The ~ 10 % of fluid is recycled back into the systemic circulation via the
lymphatic vessels. The net capillary filtration rate is equal to the rate of
lymphatic fluid flow. There is no accumulation of excess fluid in the interstitial
space.
If fluid builds up in the interstitium due to a disturbance of
capillary/lymphatic dynamics, edema is the resulting named condition. Edema
increases the diffusion distance and interferes with capillary exchange.
Peripheral edema is relatively noncritical compared with the case that the edema
occurs in the lungs (pulmonary edema), when lung oxygenation will be reduced.
occurs in the lungs (pulmonary edema), when lung oxygenation will be reduced.
The lymphatics also maintain the interstitial oncotic pressure at a minimum
mmHg. Some plasma proteins do leak and trickle out of the microcirculation.
These proteins are also drained through the lymphatics and added back into the
systemic blood circulation. Should the oncotic pressure in the interstitium
increase, this can also potentiate the development of edema.
Impaired lymphatic drainage occurs in different situations, e.g., surgical
removal for malignancy, in filariasis when the parasites infect the lymphatics.
Lack of muscle activity also reduces the compression of lymph vessels and
lymphatic circulation, as it occurs in an obedient soldier standing at attention.
The lymphatic vessels have one-way valves for the unidirectional flow of
fluid and proteins. The smaller lymphatic vessels merge into larger lymphatics,
and finally into the largest lymph conduit, the thoraic duct, that empties into the
large veins. Lymphatics also have contractile smooth muscle wall that helps to
propel lymphatic flow. This “myogenic” lymphatic “pump” is further enhanced
by innervation from the excitatory sympathetic nerve.
8. What is the value of the lymphatic flow per day?
Answer
About 3 l/day.
Concept
Knowing some quantitative aspects of physiology is very helpful in appreciating
the homeostatic dynamics in the human body. Functionally, there are four
physiologic circulations namely the systemic, the pulmonary, the capillary
microcirculation and the lymphatic flow.
Systemic circulation has a value per day of (5 l × 60 × 24) 7200 l of blood
flow daily. This would be the same for the pulmonary circulation since the left
and the right ventricular pumps are arranged in series in the closed circulatory
loop of the entire cardiovascular system.
At the capillaries, the microcirculation refers to the general capillary
filtration and capillary reabsorption circuit. This capillary dynamics serves as the
essential function of capillary exchange at the tissues. On average, 20 l of
plasma fluid per day are filtered. As a percentage of total plasma flow per day,
this works out to be just a small percentage of less than 1 %. Total plasma flow
is ~ 60 % of 7200 l/day which gives 4320 l/day. The capillary filtration is
20/4320, which is 0.46 %.
Normally, about 90 % of capillary filtrate is reabsorbed into the venular end
of the capillaries. The balance 10 % of excess fluid is flushed out by the
lymphatic drainage and returned to the systemic circulation. An edema from an
accumulation of fluid in the interstitial space is prevented. Of the 20 l of plasma
fluid filtered/day, about 3 l of fluid flow back via the lymphatic vessels.
Three liters might not seem like a lot of fluid volume. In a 70 kg male adult
with a total body water of 60 % of body weight at 42 l, around 15 % of the total
body water is in the interstitium, i.e., 0.15 × 42 l giving 6.3 l.
When we work out this value for interstitial fluid (ISF), it is clear that 3 l of
daily lymph fluid represent almost half of the total ISF volume. Obviously, an
edema easily develops if the lymphatic circulation is reduced.
The student should note that the normal blood volume in the 70 kg
physiological male standard is 5 l. The 3 l of lymphatic flow/day is the entire
plasma volume!
Four cheers to the four integrated physiologic circulations!
CARDology! We can think of several As essential in cardiovascular functions. Autonomic nervous system,
adrenaline, angiotensin II, atrial natriuretic peptide, arteriolar radius regulation, adrenal glucocorticoids,
antidiuretic hormone
9. How is capillary dynamics different in the GI tract compared to skeletal
muscle
Answer
The GI tract has both a variety of digestive secretory and absorptive functions.
Both these events will involve capillaries and a different balance of the capillary
exchange Starling’s forces.
exchange Starling’s forces.
Concept
The secretion of digestive juice by the epithelial cells of glands along the GI
tract involves fluid movement from the capillarized gland into the lumen and
eventual empyting into the GI tract. The aqueous medium of all secretions is
derived from the blood capillaries that supply the glands. Osmotic gradient
generated by prior solute secretion drives the water movement during the
secretion. The net Starling’s forces along these capillaries must be suited to
favour filtration.
Conversely, intestinal absorption of water also follows solute absorption that
creates the local osmotic difference between the lumen and the interstitium.
Water is then absorbed both trans-and paracellularly into the capillaries.
Thus, for this absorptive function to be effective, the balance of the
Starling’s forces along the length of the capillary should favour fluid
reabsorption.
In the pathophysiologic case of “dumping syndrome” due to excess
hyperosmotic food in the intestine, an abnormal secretion of fluid occurs into the
lumen (hypovolemia results) In skeletal muscles, the normal profile of capillary
filtration at one end and reabsorption at the other end downstream is altered,
when the blood volume and blood pressure falls. The capillary hydrostatic
pressure is decreased by the systemic hypotension and also by the reflex
sympathetic vasoconstriciton of the precapillary arterioles.
This reduction in capillary blood pressure changes the profile of the
Starling’s forces, and absorption of fluid along the length of the capillary is
observed. This inwards transcapillary shift of fluid is part of the compensatory
events that helps to maintain the vascular volume during hypovolemia.
10. Why are the delicate thin walled capillaries not easily prone to rupture?
Answer
The relative insusceptibility of the capillaries to rupture is due the operation of
Laplace’s Law that explains the protective effect of the small radius of the
capillaries.
Concept
The physical principle explained by the law of Laplace states that the tension in
the wall of a cylinder (T) is equal to the product of the transmural or distending
pressure (P) and the radius divided by the wall thickness (w).
Since the interstitial pressure is low, the trasnmural pressure (pressure
difference across the wall) is basically the intraviscus pressure. If the viscus is
thin walled, the w factor is also insignificant and can be ignored.
In a cylinder such as a blood vessel, Laplace’s equation becomes
As such, the smaller the radius of the blood vessel, the less is the tension in
the wall that is required to balance the distending pressure. For example, in the
human aorta, the tension at normal pressures is about 170 kdynes/cm and in the
vena cava, it is about 21 kdynes/cm.
In contrast in the capillaries, it is only 16 dynes/cm.
This law of Laplace also explains the problem associated with a dilated
heart. When the radius of the ventricular chamber is increased, a greater tension
must be developed in the myocardium in order to generate the same
intraventricular pressure. The failing heart is weakened further by the increased
cardiac work needed.
In the lungs, the Laplace’s law also accounts for the observation that in the
absence of surfactant, the smaller alveoli tends to collapse under the effect of the
alveolar surface tension.
Pee wee! Laplace also has something to say about our urinary bladder. As
the bladder is filled, the tension increases. The first urge to void is felt when the
bladder volume is about 150 ml. The next marked sense to void a full bladder
happens at about 400 ml. The small change in intrabladder pressure between the
two volumes is due to the increasing radius that balances the increasing wall
tension as the bladder fills.
© Springer International Publishing Switzerland 2015
Hwee Ming Cheng, Physiology Question-Based Learning, DOI 10.1007/978-3-319-12790-3_5
5. Regional Local Flow Regulation
Hwee Ming Cheng1
(1) Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
Hwee Ming Cheng Email: chenghm@ummc.edu.my
“Ask it shall be given.” The heart and the peripheral organs it supplies is like a
mother and her children. The mother heart is the source of all sustenance, its
oxygenated and energy substrate-richblood (cardiac output). Some of the organs
are more demanding;at rest, more blood flow/weight of the organ. There is
anunequal distribution of cardiac outputto the different organs. In specific
situations,there is a redistribution of cardiac output based on the differential
functional needs of the organs. In general, a greater demand for oxygen/energy
by a particular organ will lead to an increased blood flow to that tissue. The
mother heart pampers all her children and gives more of its generous life-giving
output to whichever organ that ask for more! Let us look at some scenarios in the
body that illustrates this cardiovascular “ask and it shall be given” principle.
1. How does the heart muscle ensure that it receives more blood when it is
more active?
Answer
Increased cardiac metabolism releases vasodilator metabolites that provide the
greater coronary perfusion commensurate with the needs of more active heart
pump.
Concept
The cardiac muscle has its own self-regulating intrinsic mechanisms that ensure
that the myocardium has adequate blood perfusion for its essential function. At
rest, when the blood pressure fluctuates over a certain physiological range,
autoregulatory mechanisms maintain a relatively constant coronary flow.
autoregulatory mechanisms maintain a relatively constant coronary flow.
When the heart becomes active during physical activity (or by emotional
stimuli), the heart pumps faster and more strongly under the action of both
cardiac sympathetic nerve and circulating adrenaline.
Coronary blood flow increases in tandem with the higher cardiac metabolic
needs when a bigger cardiac output is ejected. The increased coronary flow,
however, is not due to any direct sympathetic vasodilator nerve. Adrenaline
might dilate some vessels by its action on any vascular beta adrenergic receptors.
The coronary vasodilation is primarily due to increased local metabolite
vasodilators in the myocardium. The cardiac sympathetic action by its
tachycardic and inotropic actions increases the cardiac metabolism. Thus, the
effect of sympathetic action in increasing the coronary perfusion is indirect via
the metabolite vasodilators. One such established vasodilator is the adenosine
tri-phosphate (ATP) metabolite, adenosine. This phenomenon of metabolicdriven perfusion of the myocardium is also termed “active hyperemia.” There is
also “reactive hyperemia” resulting from the compression of coronary
vasculature especially by the strong left ventricular muscle contraction.
2. At rest, which organ is the most “demanding” and receives the highest rate of
blood flow?
Answer
The pulmonary blood flow is the cardiac output from the right “heart”
(ventricle).
Concept
The pulmonary blood circulationis in series with the systemic circulation.
Therefore, the cardiac output, defined as from each ventricle (both ventricular
pumps in series) is the same from each side of the twin-engine heart.
Changes in pulmonary blood flow during physical activity are obviously not
for the purpose of supplying more oxygen to the lungs! (Bringing coal to
Newcastle, or in Malaysia we might say,“Bringing palm oil to Kuala Lumpur!”)
The circulatory purpose of increased pulmonary blood flow during exercise is to
deliver a higher rate of oxygen to the cells (ml oxygen per time). This is partly
due to more lung oxygenation. However, since maximum oxygenations is
“perfusionlimited” (see Part 2 “Respiratory Physiology”), the greater pulmonary
blood flow is critical for a higher rate of O2 supply to the tissues.
Vasodilation of the pulmonary vessels during increased pulmonary flow is
not due to neuralor metabolite actions. (Hypoxia actually produces a unique
vasoconstriction in the lungs; see Part 2 “Respiratory Physiology”). Pulmonary
vascular resistance is decreased duringexerciseassociated with increased
vascular resistance is decreased duringexerciseassociated with increased
pulmonary blood flow. The greater right ventricular cardiac output directly
distends the pulmonary vasculature in what could be termed “mechanical
vasodilation.”This is a major vascular event when the pulmonary arterial
pressure is higher as the pulmonary vessels are relatively compliant.
Regulatory sympathetic neural actions on vascular arterioles have a dual compensatory effect. The arteriolar
vasoconstriction increases the total peripheral resistance, a determinant of blood pressure. The
“downstream” effect of the vasoconstriction on decreasing capillary hydrostatic pressure favors a reverse
transcapillary shift of fluid to restore blood volume
3. How does the brain maintain its blood supply when there is a drop of
30 mmHg in arterial blood pressure?
Answer
Cerebral autoregulation of flow in conjunction with baroreflex support of arterial
blood pressure maintains the blood supply to the brain.
Concept
The intrinsic autoregulation of blood flow is operative over the range between 60
and160 mmHg. This indicates that if the blood pressure rises above or drops
below 100 mmHg,the cerebral perfusion is autoregulated to sustain a relatively
unchanged blood flow.
In reality, two reflex mechanisms are activated in concert to preserve the
cerebral perfusion. Centrally, the baroreceptors will detect the hypotension and
trigger cardiac and vasculararteriolar constriction to raise the decreased blood
pressure.
At the same time, at the local brain tissues, the cerebral arterioles will
vasodilate. This cerebral vasodilation cooperates with the baroreflex action on
the blood pressure, and the brain continues to receive relatively normal blood
flow.
The cerebral autoregulatory response is mediated by similar mechanisms to
the autoregulation at the coronary circulation. One is the myogenic arteriolar
response. The smooth muscle of the cerebral arterioles vasodilates when it
senses less stretch by the hypotension.Secondly, a metabolic mechanism comes
into play.Initial decrease in cerebral flow, before autoregulation kicks in, causes
a build-up of vasodilator metabolites. Local increase in PCO2, localhypoxia and
lower pH in the brain tissue also contribute.
There is a marginal ~ 20 % decrease in cerebral blood flow in the presence of
autoregulation. A third physical mechanism maintains the cerebral perfusion
pressure. The arterial level at the head level drops about 30 mmHg, but the
jugular venous pressure decreases 5–8 mmHg. The drop in perfusion pressure is
reduced.
Because the cranial volume is fixed, a decrease in the venous pressure lowers
the intracranial pressure. The latter decreases the external pressure on the
cerebral vessels, and the cerebral vascular resistance is lessened.
4. What is the main determinant of blood flow to the skeletal muscle at rest and
during exercise?
Answer
At rest, the sympathetic vasoconstrictor innervations set the muscular blood
flow. During exercise, the predominant regulator of increased muscle flow is
local vasodilating conditions in the muscles.
Concept
As in almost all tissues, the arterioles that control inflow of blood in to the
capillaries of the organs are innervated by the sole sympathetic vasoconstrictor
adrenergic nerves.
At rest, this neural basal input sets the baseline for skeletal muscle flow.
The blood flow increases markedly during physical activity. Is this due to a
withdrawal of sympathetic vasomotortone as in the baroreflex response
tohypertension?
Although the blood pressure is higher during exercise, there is no reflex
bradyardia. Obviously, the exercise tachycardia is the natural expected event
from stimulation by cardiac sympathetic nerve. We can expect the same for the
sympathetic nerve activity to the arterioles of the muscles. There appears to be a
resetting of the baroreflexso that in the exercise hypertension and tachycardia
can sustain the increased cardiac output and blood flow to the muscles.
Are there then vasodilator nerves to the muscles? In some mammals, the
cholinergic sympathetic nerves have been described that seem to be involved in
cholinergic sympathetic nerves have been described that seem to be involved in
the initial increase in exercise (or even pre-exercise expectation) muscle blood
flow.
When muscle contractions are in progress, local changes in the tissue
environment feedback to increase the blood flow. These include local
hyperkalemia (from more action potentials), hypoxia, increased PCO2, and lower
pH (lactic acisosis).
The student should not mix up the increase in outflow venous return due to
the “musclepump” with the increase in inflow skeletal muscle flow that is
effected by the diverse local vasodilatory agents.
There is a decrease in total (overall)peripheral resistance during exercise due
to the vasodilation in the muscles (cutaneous vasodilation also to lose heat).
5. How and why does the blood flow increase to the skin during a hot day?
Answer
Cutaneous vasodilation is to lose heat in order to maintainnormal body
temperature.
Concept
Body temperature is controlled by the hypothalamus thermoregulatory neurons.
The thermostatic set point of normal body temperature 37 °C is regulated by
either heatloss mechanisms of heat consecrating responses. The
hypothalamicthermocontrol neurons receive afferent inputs from both central
and skin thermoreceptors.
During exposure to hot environment, the heat loss is promoted. One major
way is cutaneous vasodilation. This results from a decrease in the activity of
sympathetic vasoconstrictor fibers to the skin blood vessels.These autonomic
nerves are adrenergic.
At the same time, sweating is triggered. Sweat glands are also innervated
bysympathetic nerves that release acetylcholine as neurotransmitter. Thus, a rise
in body temperature sets in action a concurrent reduction in vasoconstrictor
sympathetic nerve to vasodilate the cutaneous vessels and an increased
cholinergic sympathetic stimulation of sweating.
When the sweat is vaporized from the skin surface, the latent heat of
vaporization is used, and this heat extracted from the body then cools the body
temperature.
A different situation occurswhen a person is frightened and begins to have
cold clammy skin (“cold sweat”). The coldness is due to increased sympathetic
vasoconstriction of the cutaneous blood vessels. Sweating is stimulated by the
vasoconstriction of the cutaneous blood vessels. Sweating is stimulated by the
separate cholinergic, sympathetic neural pathway.
6. What is the physiologic rationale for a decrease in renal blood flow during
hypovolemia?
Answer
Reduction in renal blood flow during hypovolemia is part of the compensation to
restore blood pressure and blood volume.
Concept
At rest, about 20 % of cardiac output is distributed to both kidneys. This is a
relatively large regional blood flow with respect to the mass of the renal tissues.
Besides supplying oxygenated blood and energy substrates to the cells of the
kidneys, the renal blood flow has the primary function in channeling blood to the
nephrons for filtration.
The regulation of normal flow (BF) to the heart involves integrated central baroreflex vasoconstriction to
maintain adequate systemic perfusion pressure operating in concert with local coronary vasodilation. This
occurs, e.g., during hypovolemia. In exercise hyperemia, selective vasoconstriction occurs in
splanchnic/renal vasculature with vasodilation in the skeletal muscles and the skin (to lose heat) besides
increased coronary perfusion
Compared to the 1 % of plasma filtered in other capillaries, the glomerular
capillary has a filtration fraction (glomerular filtration rate, GFR/renal plasma
flow) of 20 %.
During hypovolemia, the blood pressure is also decreased. The kidneys have
a key role in blood volume control, and this is linked to its homeostatic function
in blood pressure regulation. The students need to review and appreciate that
extracellular fluid (ECF)/blood volume control is integrated into the renal
handling of sodium and regulation of sodium balance.
Hypovolemia triggers a general increase in sympathetic discharge and this
includes increased renal sympathetic nerve (RSN) action. The RSN’s overall
includes increased renal sympathetic nerve (RSN) action. The RSN’s overall
action in the kidneys is to conserve sodium together with effects to restore
volume and blood pressure.
Vasoconstriction of renal arterioles by RSNis part of the compensatory
increased total peripheral resistance that is produced by greater sympathetic
neural activity.
The temporal decrease in GFR consequent from the reduced renal blood flow
is to decrease the excretion of sodium and conserve body sodium to recover the
volume. Filtered load of sodium is reduced when the GFR drops.
The kidneys excrete less sodiumalso because the RSN acts to increase the
tubular reabsorption ofsodium. This is via stimulating the release of renin from
the juxtaglomerular endocrine cells of the afferent arteriole. RSN also has direct
action on proximal tubular sodium reabsorption.
7. What is vasovagal shock?
Answer
This is a neurogenic shock when a sudden change, burst, or outflow of
autonomic neural activity produces vasodilation, pooling of bloodin the
extremities, and the person faints.
Concept
Vasovagal, neurogenic shock is one of three types of what is categorized as
distributive shock (Ganong, 2nd edition, p. 637). The other two are anaphylaxis
and sepsis. Distributive shock is also called “warm shock,” because the skin is
not cold and clammyas seen in hypovolemic shock. In distributive shock, the
blood volume is normal, but there is amarked sudden vasodilation.
Fainting is, of course, non-life threatening and only short-lived. The
horizontal position postfainting is in a real physiologic sense a “homeostatic
mechanism,” because the supine person will have improved venous return,
cardiac output, and cerebral perfusion.
Other triggers ofsyncope are: postural syncope in patients with orthostatic
hypotension. Micturition syncope, fainting during urination that is due to a
combination of orthostasis and reflex bradycardia activated by voiding urine in
these patients (voiding can belike a mild Valsalva!). Cough syncopetakes place
when the forced expiratory coughingincreases the intrathoracic pressure and
impede venous return.
The carotid sinus syncope is produced when a tight collar presses on the
carotid baroreceptors and produces the reflex bradycardia and vasodilation.
In neurogenic vasovagal shock, there would be a burst of vagal
parasympathetic to the cardiac pacemaker sinoatrial (SA) node (bradycardia) and
parasympathetic to the cardiac pacemaker sinoatrial (SA) node (bradycardia) and
a decreased in sympathetic vasoconstrictor activity to the arteriolar vessels
(vasdodilation). There could be also an acute outflow of vasodilator sympathetic
pathways. Vasovagal syncope occurs in situations of intense emotional stimuli.
The syncope can be due to serious underlying abnormalities, and all cases of
syncope must be investigated. About 25 % of syncopal episodes are due to
cardiac causes, e.g., transient intracardiac flow, cardiac arrhythmias that
acutelydecrease the cardiac output.
Since here, there is an overlap with cardiogenic shock that is described also
as neurocardiogenic shock.
The inquiring students may ask “Why is the vasodilationin distributive shock
an adverse event? Would not the blood flow to the tissue be better?” Here the
overall hemodynamics of the cardiovascular system needs to be recalled.
The arterial blood pressure is determined by the cardiac output (CO) and the
total peripheral resistance (TPR). The blood pressure must be maintained for
continuous, adequate effective circulating blood volume to the tissues. A
reduction in the CO determinant happens in cardiogenic shock. Asudden drop in
the TPR will cause the blood pressure to fall. The brain is deprived of sufficient
cerebral perfusionand the person faints.
8. How is anaphylactic shock and septic shock similar in their pathophysiology
of circulatory failure?
Answer
Both anaphylactic and septic shockare conditions classified under vasogenic
circulatory shock.
Concept
Anaphylactic shock results from a severe allergic hyperreaction to a culprit
antigen that the person has been previously sensitized. The antigen–antibody
allergic reaction results in the release of histamine from some white cells.
Circulating histamine produces the widespread vasodilation of arterioles and
abnormal increase in capillary permeability.
In septic shock, a serious infective condition due usually to gram-negative
bacteria leads to features of vasogenic and hypovolemic shock. Endotoxins, the
cell wall polysaccharides act to cause systemic vasodilation. The capillary
permeability is also disrupted, and the plasma fluid enters the interstitial space
with the reduction of plasma protein oncotic pressure.
The vascular volume is contracted, and this hypovolemia worsens the initial
vasogenic, septic circulatory shock.
vasogenic, septic circulatory shock.
A similar vasogenic/hypovolemic shock is seen in dengue hemorrhagic
shock. The pathogenesis of dengue viral infection involves the release of many
chemical mediators that are part of the body’s immune response. Some of these
cytokines disturb the capillary functional integrity. Plasmafluid and proteins leak
out easily. The dengue picture at this stage is of a person bleeding into his
interstitium. There is hypovolemia as a result.
In irreversible circulatory shock, compensatory mechanismsfail to restore the
normal blood pressure. Permanent impairment of the blood pressure
maintenance machinery has occurred.
If severe hypovolemia was the precipitating cause, ischemic damage to the
intestinal tissues can permitthe enteric microflora to enter the systemic
circulation.
Some of these commensal bacteria that are now in the blood circulation can
be the cause of a vasogenic shock.
9. How does the concurrent stimulation of sympathetic nerve to the heart and to
specific blood vesselshelp to redistribute cardiac output?
Answer
Cardiac output is increased by sympathetic stimulation. Selective sympathetic
vasoconstriction at the regional organs redistributes the increased cardiac output
during exercise.
Concept
The regional, local circulation to the individual organs are generally arranged
inparallel to each other. This allows specific local control of flow without
affecting the perfusion to other organs which will be the case if the organs are
linked by the blood circulationin series with each other.
During physical activity, the cardiac function is increased by sympathetic
stimulation with a higherheart rate and stroke volume. The skeletal muscles
require more of the greater cardiac output. There is a channeling of more blood
flow to the muscles with a relative reduction to the splanchnic and the renal
circulations. This illustrates the selective vasoconstriction at the renal and the
splanchnic by sympathetic neural action.
During exercise, heat loss mechanism involves cutaneous vasodilation. Increased muscle activity produces
vasodilator metabolites and local hypoxia to increase skeletal muscle blood flow. The overall total
peripheral resistance (tpr) is decreased. This reduced tpr has the effect of lowering the diastolic blood
pressure which is due to the arterial vascular recoil
In the hypovolemic situation, there is also selective sympathetic vascular
effects. This again includes a decrease in the renal, splanchnic, muscle, and the
cutaneous perfusion. The latter accounts for the “cold clammy skin” during
hypovolemia (clammy due to sympathetic nerve to sweat glands).
In exercise, to regulate body temperature, the cutaneous arterioles are
vasodilated by a decrease in sympathetic vasoconstrictor activity. Also, during
muscle contraction, the actions of local vasodilating conditions/metabolites
predominate over any increased sympathetic nerve input to the skeletal muscles.
In hypovolemia, the selective sympathetic action results in an elevated total
peripheral resistance in order to restore blood pressure.
In contrast, the selective vasoconstriction at the renal and splanchnic
vasculature is exceeded by the vasodilation at the muscles and the skin. Overall,
the TPR is decreased. The higher blood pressure in exercise is sustained by the
cardiac sympathetic actions.
10. How does severe diarrhea and burn shockaffect local blood flow?
Answer
Both severe diarrheaand burn shock produce hypovolemic shock. Diarrhoea
results in an isotonic contraction of the ECF and in burns, there is
hemoconcentration since the plasma is lost from the burned surfaces.
Concept
Hypovolemic shock includes, depending on the cause, hemorrhagic shock,
traumatic shock (where blood bleeds into injured muscle/bone tissues), and the
loss of fluids due to vomiting or diarrhea.
In hemorrhagic and traumatic shock, whole blood transfusion replaces the
vascular volume loss. Saline can also be used. However, saline is distributed into
vascular volume loss. Saline can also be used. However, saline is distributed into
the whole ECF, and thus, only a quarter of the saline volume replenishes the
vascular space.
In burn shock where there is hemoconcentration, plasma transfusion is the
treatment of choice. There are also “plasma expanders,” that are solutions of
high-molecular weight sugars that remain in the vascular compartment and
actosmoactively.
In hypovolemic, and other kinds of circulatory shock, insufficient perfusion
of the tissues leads to increased anaerobic glycolysis. If the resulting lactic
acidosis is severe, the myocardial functions can be depressed, and there can be
also a reducedvascular responsiveness to vasoactive agents like
catecholamines.The acidosis also suppresses the neuronal function, and an
acidotic coma is a potential terminal outcome.
Hypovolemia is a potent stimuli for adrenal catecholamine secretion.
Circulating catecholamines stimulate the reticular activating system in the brain
and produce the restlessness observed in some patients with hemorrhagic shock.
The restlessness has some homeostatic role since the increased muscle activity
and increased respiratory movements provide the muscle and pulmonary “pump”
effects to improve the venous return.
Do not put the cart before the horse
Part II
Respiratory Physiology
© Springer International Publishing Switzerland 2015
Hwee Ming Cheng, Physiology Question-Based Learning, DOI 10.1007/978-3-319-12790-3_6
6. Airflow
Hwee Ming Cheng1
(1) Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
Hwee Ming Cheng Email: chenghm@ummc.edu.my
An event taken for granted is the automatic inflow (inspiration) and outflow
(expiration) of air from our lungs. Only when the airflow is disturbed, we
become conscious of the increased effort of breathing. What drives inspiration
and expiration, and what airway parameters affect airflow? How much of the
new inspired air reaches the final site of respiratory exchange at the pulmonary
alveoli? Do you not think of your breath? Think through these questions.
1. What is the meaning of “negative” in the term “negative-pressure
breathing” during normal respiration?
Answer
The “negative” refers to the subatmospheric intraalveolar pressure with the
atmospheric reference pressure given the value 0 mmHg.
Tidal volume is the air actively breathed in from functional residual capacity (FRC) or passively breathed
out (broken line) to FRC. The depth of the TV (vertical axis of inverted triangle) is determined at the
respiratory “pacemaker” neuronal network in the brain stem. A deep breath is voluntarily taken by cortical
impulses that bypass the autorhythmic respiratory neurons and directly synapse with spinal motor neurons
that innervate respiratory muscles that include the diaphragm
Concept
Airflow only takes place when there is a difference in pressure. At the beginning
of an inspired breath, the atmospheric and alveolar air pressure is the same, and
no air movement occurs yet. Air moves into the lungs when the alveolar air
pressure drops to less than the atmospheric pressure (since you cannot change
the external pressure!). The respiratory mechanics basically produce this
“negative” alveolar pressure to initiate the inflow of air (tidal volume) in to the
lungs. Inspiration is an active process and begins with the contraction of
inspiratory muscle (diaphragm being the main muscle). This contractile action
makes the intrapleural pressure (Pip, between the visceral and pleural
membranes) more negative. The change in the Pip then increases the
transpulmonary pressure (difference between alveolar air and the Pip). The
greater transpulmonary pressure begins to distend the alveoli and the
intraalveolar pressure decreases to below the atmospheric pressure (below
0 mmHg of 760 mmHg).
Alveolar ventilation (V A ) replenishes the alveoli and V A is determined by the tidal volume and the
frequency of breathing. In patients, compensatory effort to maintain alveolar ventilation is seen in shallow
(low TV), rapid (high frequency, F q ) breathing or slow (low F q ), labored (high TV) breathing
2. What prevents the lungs from collapsing even with the maximal expiratory
effort?
Answer
The opposing outward recoil of the chest wall to the inward recoil of the lungs.
Concept
The lungs are expanded from birth (when we cry out and make our first voice to
the world!).The lungs and the chest wall are anatomically apposed intimately
with each other, separated by a very thin pleural space. Given a chance, the
lungs will tend to collapse inwards. Even at the end of a normal breath
(expiration). The tendency of the lungs to recoil inwards is balanced by the equal
and opposite outward recoil of the chest wall. This generates a negative Pip in
the pleural space. In situations when there is physical trauma and air enters the
pleural space (pneumathorax), the lungs will be held open longer by the chest
wall.
When we do a voluntary force expiration, the lungs do not empty
completely, and the minimum lung volume is the residual volume. At this
volume, the outward recoil of the chest wall is increased and higher than at the
lung volume after normal expiration (functional residual capacity, FRC). With a
maximal inspired effort, the lung volume reaches the total lung capacity (TLC).
At TLC, the chest wall recoil is inwards, in the same direction as the recoil of the
elastic lungs. The chest wall mechanic is slightly different as it is a rigid
structure and the direction of recoil can change depending on the position of the
chest wall (a good illustration is the breast bone of chicken; press it inwards and
it spring outwards; stretch it outwards and it will recoil inwards. Try it and think
about FRC and TLC the next time you eat at a KFC!)
3. How does the alveolar pressure and Pip compare at the beginning and end of a
breath?
Answer
The alveolar pressure at the start and end of inspiration is the same as the
atmospheric pressure. For the Pip, it becomes more negative.
Concept
The student needs to think about pressures when thinking through lung function.
There are four different pressure terms to use when describing how each of them
changes during a respiratory cycle. The card showing four of clubs is a helpful
reminder, the club resembling like the pulmonary alveoli! Physiology texts will
show a graph of these pressure changes during inspiration and expiration. The
four pressures are alveolar pressure, Pip, atmospheric pressure and
transpulmonary pressure. The alveolar pressure should be the same as
atmospheric pressure at the beginning and end of inspiration (or end and start of
expiration, respectively). The Pip is always negative at rest. During a respiratory
cycle, it becomes more negative during inspiration when the inspiratory muscles
contract. During expiration, it returns to its negative preinspiratory value. The
transpulmonary pressure is the transmural pressure (mural means wall, in this
case, the alveolar wall) that is calculated. It is the expanding or distending
pressure, and the value is the difference between the intraalveolar pressure and
the Pip. Thus, the transpulmonary pressure is the highest at the end of normal
inspiration (a tidal volume has entered the lungs) when the Pip is most negative
and the alveolar pressure is 0 mmHg.
Humans inspire by negative-pressure breathing. The alveolar air pressure becomes negative
(subatmospheric at ref 0 mmHg). Inspired tidal volume then enters the lungs down the atmospheric-alveolar
pressure gradient. The “negative” P alv is achieved when the inspiratory muscles contract and make the
intrapleural pressure more negative. As such, the transpulmonary pressure increases and expands the alveoli
and the P alv becomes negative
4. How is the rate of airflow related to airway radius in a single airway?
Answer
Airflow is proportional to the airway radius to the power of 4.
Concept
The aerodynamic principle in airways is the same as the hemodynamic
relationship in blood vessels. Airflow (F) is a single airway which is
predominantly affected by changes in the airway radius (r). The airway
Resistance® is inversely related to the power of 4 of the radius. This means that
if the airway radius is halved, the airway resistance is increased by 16 times.
Since F changes proportionately with R, the airflow will then increase or
decrease markedly, in parallel with the power of 4of the radius. The airway has
smooth muscles. The bronchoconstriction or bronchodilation occurs
predominantly in the noncartilaginous segment of the respiratory tree. An
autonomic parasympathetic nerve releases acetylcholine that produces
bronchoconstriction, while the sympathetic nerve action acts on beta adrenergic
receptors to increase the airway radius (persons with a history of asthma
commonly have their handbag/pocket an inhaler containing a beta receptor
agonist). It should be noted that a large part of sympathetic bronchodilatory
effects is mediated indirectly via stimulation of adrenaline secretion from the
adrenal medulla by the sympathetic nerve. The circulating adrenaline acts on the
same beta receptors on airways as the neurotransmitter noradrenaline released by
the sympathetic adrenergic nerve to the airways.
The word single in the question is italized for an important reason. When we
consider respiratory aerodynamics or vascular hemodynamics, the principle is
applied to a single air or blood conduit. When we take the whole respiratory tree
with its multiple generations of branching into smaller and smaller airways
leading into the alveoli, the actual airway resistance is no longer inversely
related to the radius of a particular segment of the respiratory tree. Branching of
airways into parallel flows down the smaller airways, increases the total cross
sectional area of the air passages, and has the effect of decreasing the
downstream regional airway resistance. Thus, the highest airway resistance is
not located at the deepest part of the respiratory tree with the smallest airways.
Note, however, that the airflow ml air per min in each of the lungs should still be
the same at every generation of the respiratory tree.
5. How is spirometry used to assess the major airway parameter that affects
airflow?
Answer
Spirometry assesses the airway resistance by measuring the forced expiratory
volume in one second FEV1.0.
Concept
Spirometry is able to determine lung volumes and lung capacities except the
residual volume (RV). Since FRC and TLC include the RV, the FRC and TLC
are not determined by spirometry either. The forced expiratory volume is
basically a forced vital capacity measurement. Vital capacity is obtained by
asking the patient to breathe in maximally and then from TLC, to breathe out
maximally to RV. For a forced VC, the expiratory phase is done by the patient as
forcefully and as rapidly as possible. The volume of the vital capacity that can be
expelled by the forced expiratory effort in the first second is then noted. For a
healthy lung with normal airway resistance, the FEV in one second should be at
least 70 % of the vital capacity (VC). For increased airway resistance, e.g.,
asthma, the FEV1.0 will be less than 70 %. Pulmonary disease is clinically placed
under two categories, namely obstructive and restrictive lung dysfunction. The
definition of an obstructive pulmonary condition is when there is an abnormal
increased airway resistance. Thus, the FEV1.0 spirometry is commonly
performed in patients with asthma and other obstruction lung disease. The
restrictive lung problems are due to a characteristic reduced lung/chest wall
compliance. Any pathophysiologic or anatomical situations that restrict the
normal expansion of the lungs are called “restrictive.”Words and definitions can
sometimes be unhelpful in understanding the physiology. A student can, not
incorrectly, view increased airway resistance in obstructive pulmonary disease as
“Restricting” the airflow!
6. How does a slow, deep inspiration affect airway resistance?
Answer
Airway resistance decreases with increasing lung volume.
Concept
The main parameter that determines airway resistance is the airway radius.
Airway resistance is inversely related to the power of 4 of the radius. One of the
pressure that alters airway radius is the transmural pressure across the wall of the
airways. This airway transmural pressure is the difference between the pressure
in the airways and the pressure outside the airways, i.e., the Pip. The transmural
pressure is a distending pressure. The higher the transmural pressure, the larger
the radius will increase, and consequently the airway resistance will decrease. A
deeper breath or increased tidal volume is achieved with a greater voluntary
inspiratory effort. This is associated with an increased negativity of the Pip. The
airway transmural pressure is then greater and the airway resistance lower. This
makes physiologic sense since when we feel encouraged and feel “inspired to
inspire” deeply, a larger volume of fresh air is more easily taken into the lungs!
The italicized “slow” in the question also makes an aerodynamic point. An
increased airflow velocity tends to increase the resistance to airflow due to
turbulent airflow. So a hurried maximal inspiration will not reduce the airway
resistance as much as a leisurely deep breath. In patients with obstructive lung
disease, there is pathophysiologic elevated airway resistance. Characteristically,
the patient’s breathing pattern is slow and deeper. The slower, labored breath
partly helps to avoid adding to the airflow resistance load. If you believe in the
benefits of the Chinese physical exercise tai chi, think of the slow, relaxed, deep
breathing that accompanies some of the movements!.
7. How does the transpulmonary pressure vary in an upright lung at the end of
normal expiration?
Answer
In an upright lung, the transpulmonary pressure at the end of a normal expiration
increases progressively from the base to the apex of the lungs.
Concept
The transpulmonary pressure is the transmural pressure at the alveolar wall. In
the upright lung, the Pip is affected by gravitational force. The Pip is no longer
the upright lung, the Pip is affected by gravitational force. The Pip is no longer
the same at every level of the lungs from the base to the apex. Due to the weight
of the lung tissue, the Pip at the base of the lungs is less negative than the apex
of the lungs. This translates to a higher transpulmonary pressure at the apex than
at the basal alveoli at the end of a normal expiration (FRC). The size of the
apical alveoli are bigger than the basal alveoli. However, alveolar ventilation is
not reflected in the alveolar size at FRC. What is important in ventilation is how
much of the next tidal volume (fresh, inspired air) is distributed to the different
regions of the upright lung. The larger apical alveoli are surprisingly less
compliant than the basal alveoli (In physiology text, the apical alveoli are shown
as located on the upper plateau portion of the lung compliance curve, whereas
the basal alveoli are sited at the more compliant steep slope of the curve.). Thus,
more of the tidal volume actually is distributed to the more dependent part of the
lungs, i.e., these alveoli are more ventilated or replenished with new, inspired
air. What does all this mean in terms of respiratory function? Is this just a trivial
detail of no consequence? The different degree of alveolar-ventilated parts of the
normal, upright lungs will affect the oxygenation, since the pulmonary blood
flow in the upright lung is also affected by gravity (oxygenation is dependent on
the ventilation/perfusion or V/Q matching). I tell my students after they have
understood how alveolar ventilation is better at the base of the upright lung,
“things are not always better at the top!”
8. What are the two major factors that contribute to lung recoil?
Answer
Lung elasticity and alveolar surface tension.
Concept
The work of breathing, when airflows require energy. The energy is expended as
airflow against airway resistance and against the opposing elastic force to
alveolar expansion. One major normal resistance factor to lung expansion is the
lung recoil force. The lungs are expanded from birth ex utero and the lungs
always have an inward recoil tendency to collapse into its natural deflated state.
Lung recoil is due to its elasticity. Any physiological structure that is elastic has
an elastic recoil. Thus, the elastic recoil opposes distention or stretch (this use of
the word “elastic” is different from common usage that means an elastic item,
e.g., pajamas are easily stretchable!). The second component of lung recoil is the
surface tension force of the alveoli. The surface tension (ST) force is due to the
thin layer of fluid that lines all alveoli. The water–air interface accounts for the
ST force. So when the alveoli expands, they expand against the elastic recoil and
the recoil surface tension force. The essential pulmonary surfactant has a STlowering action and produces the alveoli stability that prevents ST force from
collapsing in particular, the smaller alveoli at the end of normal expiration. The
relationship between alveolar ST, the radius of the alveolus and the distending
pressure needed to keep it expanded is given by Laplace’s law. In premature
babies, the pulmonary surfactant is deficient and the lung recoil of the baby’s
lungs is high due to the greater ST force. The babies suffer from breathing
difficulty, described as “respiratory distress syndrome.”
9. Which two changing parameters determine the alveolar ventilation?
Answver
Tidal volume and frequency of breathing
Concept
Not all the volume of each inspired air (tidal volume) reaches the alveoli where
respiratory gases are exchanged. Part of the respiratory tree serves as conducting
conduits for the airflow besides protective and immune defence functions (the
lungs are in direct exposure to any harmful environmental stimuli. This
nonrespiratory space is called “anatomical dead space” (ADS, the “dead” is an
unfortunate term for a living functional part of the lungs). To calculate
ventilation of the respiratory zone (“alveolar ventilation”), the tidal volume
minus the ADS is multiplied by the frequency of breathing. The ADS is roughly
equal to the person’s body weight in pounds. Compared to the changing values
of tidal volume and respiratory rate, the ADS is relatively unchanged. For
patients with poor tidal volume (restrictive lung disease), since the ADS is fixed,
a reduced volume of each breath reaches the alveoli exchange area. Thus,
characteristically, the patient has compensatory increased breathing rate. The
breathing is described as shallow and rapid. For those who enjoy snorkeling and
admiring created beauty under the sea, the breathing tube represents an extension
of the ADS in the snorkeler! The depth of submersion underwater during
snorkeling is, thus, limited by the need for adequate alveolar ventilation. Those
who are stimulated watching medical dramas will hear about the emergency
surgical procedure called “tracheostomy”. For persons who developed acute
respiratory failure, the tidal volume drops markedly. The tracheostomy
surgically reduces the ADS and aids to sustain the airflow and oxygenation at
the alveoli.
Not all the air in a tidal volume reaches the alveolar respiratory zone. The alveolar air PO2 is an equilibrium
between fresh, high PO2 inspired air and the diffusion of oxygen into pulmonary alveolar capillary blood
10. What accounts for the abnormal lung compliance in emphysema?
Answer
Destructive loss of elastic tissues.
Concept
Emphysema is an obstructive lung disease that is accompanied by destruction of
lung tissues. The loss of lung tissue included elastic structures. This leads to less
elastic recoil of the emphysematous lung. Lung compliance is defined as the unit
change in lung volume per unit change in transpulmonary pressure. Compliance
is thus distensibility. Since elastic recoil of the lung opposes lung expansion,
lung compliance is inversely related to its elastic recoil. The emphysematous
lung, therefore, has an abnormal increased compliance (the pulmonary
compliance curve is shifted to the left). In emphysema, supporting tissues that
help to keep the airway patent are also destroyed. This results in the tendency for
help to keep the airway patent are also destroyed. This results in the tendency for
the airway to collapse, especially during expiration and increasing the airway
resistance. With chronic emphysema, the phenomenon of “airtrapping” occurs
with the markedly elevated airway resistance during expiration. The patient will
have an enlarged FRC. The distended FRC is also caused by the abnormal lung
compliance in emphysema which accommodates the “air trapping.”An important
strong contributing factor to the development of emphysema is smoking. This
detrimental lifestyle habit needs to be “emphasized” in health and wellness
education!
© Springer International Publishing Switzerland 2015
Hwee Ming Cheng, Physiology Question-Based Learning, DOI 10.1007/978-3-319-12790-3_7
7. Upright Lung, Ventilation, and Blood
Flow
Hwee Ming Cheng1
(1) Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
Hwee Ming Cheng Email: chenghm@ummc.edu.my
Lung function involves respiratory airflow and also pulmonary blood flow.
Moreover, the airflow and blood perfusion are interfaced at the alveolarcapillary membrane, where respiratory gases, oxygen, and carbon dioxide are
exchanged. The diffusion of O2 and CO2 at the lung is thus influenced not only
by alveolar ventilation but also by a matched pulmonary blood supply to the
alveoli. The lungs are relatively large structures and the body posture modifies
both the ventilation and blood perfusion at different levels above the heart in an
upright lung of a standing person due to gravitational force.
1. How does the ventilation/perfusion (V/Q) ratio change in an upright lung?
Answer
The ventilation perfusion ratio increases from the base to the apex of the upright
lung.
Concept
The alveolar ventilation is best at the base of the upright lung and decreases
towards the apex. The pulmonary blood hydrostatic pressure is also affected by
gravity. Thus, pulmonary blood flow or perfusion is also best to the basal alveoli
and lessen towards the apical alveoli. The gradient in the progressive reduction
in pulmonary perfusion is steeper than for the alveolar ventilation. Thus, the
calculated V/Q matching ratio increases from the base to the apex of the upright
lungs. For the whole lungs, the V/Q balance has a value ~ 0.8, where alveolar
ventilation is 4 L/min and pulmonary blood flow is 5 L/min, the ejected blood
flow rate (cardiac output) from the right ventricle. So, there is uneven regional
V/Q in the resting lungs. When a person does physical activity, the pulmonary
blood flow is more evenly distributed throughout the lungs and the V/Q ratio is
less uneven across the lungs. Why does the V/Q ratio matter? We can imagine
the two extremes of V/Q mismatching—zero ventilation but normal perfusion
which will give a V/Q of zero, or absence of perfusion but normal ventilation
which has a V/Q value of infinity. These two scenarios provide no oxygenation
of the pulmonary blood. Thus, the optimal crosstalk between the airflow and
blood flow is essential for effective exchange of oxygen as well as for the
adequate removal of carbon dioxide from deoxygenated mixed venous blood
from the periphery.
2. How does the pulmonary blood flow change if a voluntary deep inspiration is
done?
Answer
The pulmonary blood flow should physio-logically increase.
Concepts
In Chap. 1, we touched on the way in which increased lung volume is associated
with a decreased airway resistance which physiologically aids airflow during a
deep inspiration. The net effect of a deep inspiration is also to increase
pulmonary blood flow. The word “net” indicates that there are multiple factors
impinging on pulmonary perfusion during a maximal inspiration. A positive
effect is due to the decrease in the central venous pressure when the thoracic
space is more expanded. The venous return into the right ventricle is thus
enhanced and this provides the greater cardiac output/pulmonary blood flow to
the lungs. The effect on pulmonary vascular resistance (pvr) is a little unique and
unusual. The lowest pvr is at functional residual capacity (FRC), at the end of a
normal expiration. On either side of FRC, of lung volume decrease or increase,
the pvr increases. In some physiology texts, this is explained by the differential
changes in vascular resistance in alveolar vessels and extraalveolar vessels. The
alveolar vessels are directly subjected to the mechanical compression of the
alveolar air pressure while the radius of the extraalveolar vessels changes with
changes in the intrathoracic pressure. Thus, during a deep inspiration, the
extraalveolar vascular resistance lessens while the alveolar vessels are more
compressed by the larger alveoli. Going back to the answer and “net” effect
above, overall, there is an increase in pulmonary blood flow with a deep
inspiration. This is also called a “respiratory pump” effect and contributes to the
greater cardiac output during exercise.
The tendency for the lung to recoil is due to two factors. The elasticity of the lung tissues produces the
elastic recoil. Note that elasticity is defined physiologically as the recoil force that opposes distention or
stretch. Lung elasticity is inversely related to lung compliance. The second factor is the alveolar surface
tension, which is an inward collapsing alveolar force
For the physiology teacher, the issue is “should we teach the phenomenon of
the graphically represented U-shape pvr changes during a respiratory cycle?” Is
telling our students about the “respiratory pump” effect good enough?
Depending on the structure of each medical school curriculum and the available
time allocated for small group discussion/tutorials, the teacher will have to
decide discerningly. Do we teach more to educate, to inspire curiosity and
discovery, or merely impress our students?!
3. What is the physiological benefit of the response of the pulmonary blood
vessels to local hypoxia?
Answer
Hypoxic pulmonary vasoconstriction helps to compensate for V/Q mismatching.
Concept
The pulmonary vasculature is unique in its response to hypoxia. All other
arterioles in the body, skeletal, coronary, cerebral will vasodilate in response to
hypoxia. This aims to ensure that the muscle, heart, or brain receives adequate
oxygen. In contrast, pulmonary vessels constrict when they sense a decrease in
oxygen. The bronchial circulation supplies oxygenated blood for the metabolic
needs of the lungs. The pulmonary circulation, however, recycles blood from the
periphery to be oxygenated at the alveolar-capillary interface. In response to the
local hypoxia, the pulmonary vessels constrict, and this has the effect of
redirecting more of the blood to the alveoli that have normal PO2. Thus, if the
regional alveoli are relatively underventilated (V/Q is reduced), the alveolar PO2
will be less than 100 mmHg, and compensatory hypoxic pulmonary
vasoconstriction (HPV) occurs.
In a different situation when the V/Q is high (relatively overventilated
alveoli as when the alveoli receive a reduction in blood flow), the partial
pressure of carbon dioxide in alveolar air is decreased. The local hypocapnia will
produce bronchoconstriction of the corresponding local airways and airflow is
channeled to alveoli that are better perfused.
HPV accounts for pulmonary hypertension when there is generalized
vasoconstriction in response to hypoxia throughout the lungs. This is seen in
persons exposed to high-altitude hypoxia.
4. State reasons whether you expect the pulmonary arterial pressure to increase
much during exercise.
Answer
The pulmonary arterial pressure P pulm does not increase much as the pvr is
decreased by any increase in P pulm .
Concept
The pulmonary hemodynamics is different from that of the systemic circulation.
In systemic circulation, we have arterial blood pressure = cardiac output × total
peripheral resistance. Changes in the two determinants, cardiac output (CO) or
total peripheral resistance (TPR) will change the arterial blood pressure. The
equation is mechanistically explained generally from a left to right direction. In
the lungs, the pulmonary blood vessels are relatively compliant and easily
stretched by increasing the blood pressure. When the right heart pumps a greater
cardiac output, the pulmonary arterial blood flow is increased. We might expect
a proportionate, parallel increase in the pulmonary arterial pressure. However,
the increased volume of blood flow mechanically distends the pulmonary
vessels. In addition, some pulmonary vessels that are not fully patent at rest are
recruited to supply the increased pulmonary blood flow. These two “mechanical
vasodilation” events, vascular distention and vessel recruitment lowers the
pulmonary arterial pressure. Thus, the pulmonary hemodynamic can be said to
proceed in a left to right direction when we look at the equation, pressure = flow
× resistance; however, with the difference that any potential increased blood
pressure will decrease and not increase the vascular resistance.
The pulmonary blood vessels are relatively compliant. As such, the pulmonary vascular resistance (pvr) is
decreased when the blood pressure in the pulmonary artery increases. Pressure or mechanical distention and
recruitment of more blood vessels vasodilate, and the pvr to blood flow is reduced
5. How does the pulmonary blood flow contribute to increased oxygenation (ml
O2/min) during increased metabolic demand?
Answer
Increased pulmonary blood flow overcomes the perfusion-limited oxygenation in
the lungs during rest.
Concept
This question might appear to ask the obvious. A number of points need to be
made. First, oxygenation is different from ventilation. Oxygenation is ml
oxygen/min, whereas ventilation is simply ml air/min. Oxygenation occurs
rapidly across the alveolar-capillary membrane, down the PO2 gradient. Alveolar
air PO2 is 103 mmHg and mixed venous blood has PO2 of 40 mmHg. Complete
oxygenation at rest by net diffusion and equilibration of PO2 is achieved at less
than half the pulmonary capillary transit time (time of exposure to the alveolar
air). No further diffusion and oxygenation of blood takes place beyond the
equilibration point. More oxygenation (ml O2 per unit time) can occur if there is
more inflow of deoxygenated blood (perfusion-limited oxygenation). An
illustration to help appreciate this is as follows: Each unit of blood represents an
airplane and the alveolus is where the air passengers get on. The plane has a
limited seating capacity (103 passengers). In any given time, if there is a need to
fly more passengers to the periphery of the cardiovascular world, you simply
increase the number of your airplanes at the alveolar air terminal, since each
plane is filled up quickly by 103 passengers.
This also makes the point that during exercise, the main factor that provides
increased oxygen delivery to the cells is not hyperventilation but increased
pulmonary blood flow. Hyperventilation will only increase the alveolar air PO2
slightly and this does not result in a marked increase in saturation of hemoglobin
and the blood oxygen content (sigmoid-shape of oxygen–hemoglobin
dissociation curve, see Chap. 3.
The pulmonary blood flow is determined by the driving perfusion pressure, which is determined by
different parameters at different levels of the upright lungs. At the basal lung region, Pa—Pv drives the
flow. In the mid-region of the upright lungs, Pa—alveolar air pressure (alv P) determines the flow. At the
apex, Pa has dropped to a situation when alv P—Pa becomes the deciding perfusion pressure
6. How does the PO2 gradient component of diffusion capacity of oxygen in the
lungs (DLO2) increase during exercise?
Answer
The PO2 gradient is increased mainly due to the reduction in the mixed venous
blood PO2 due to increased metabolism.
Concept
Lung oxygenation is described by the index DLO2 which is the volume of
oxygen/min transferred across the alveolar-capillary membrane per mmHg
(mmHg here is the difference between alveolar PO2 and mean pulmonary
capillary PO2; mean because, there is no one single value as the blood PO2
rapidly equilibrates with that in alveolar air). The student might think that during
exercise, with hyperventilation, the alveolar air PO2 should be raised above
103 mmHg. However, the arterial blood and thus the alveolar air PO2 is
relatively constant during physical activity. The gradient for oxygen diffusion is
steeper due to the arrival of venous blood that is more deoxygenated (PO2 less
than 40 mmHg).
The same situation also applies to the carbon dioxide diffusion from the
pulmonary blood into the alveolar air. The alveolar air PCO2 is still about
40 mmHg. The increased production of metabolic CO2 increased the mixed
venous PCO2 to be higher than 46 mmHg, the value at rest. Note the starting
partial pressure gradient for CO2 diffusion is much less (6 mmHg) than that for
O2 (60 mmHg). This is due to the higher solubility of CO2 in blood.
The diffusion of both respiratory gases is a passive process and as described
by Fick’s law of diffusion—surface area is the other major determinant for the
passive movement of O2 and CO2. The surface area available for diffusion at the
alveolar-capillary membrane comprises the apposition of the alveolar epithelium
and the endothelial cell of the pulmonary capillary, separated by a thin
interstitial space.
7. What enzymatic action associated with the pulmonary circulation plays a role
in blood pressure control?
Answer
Conversion of angiotensin I (AI) to angotensin II (AII).
Concept
Besides gas exchange, the lungs have a number of nonrespiratory functions. One
essential reaction occurs at the endothelial cells of the pulmonary blood vessels.
This is the major location of the enzyme, angiotensin-converting enzyme (ACE).
The ACE transforms AI to the bioactive AII. AII is a multitasker peptide
hormone. AII is a potent vasoconstrictor, and this increases the TPR. In the
blood pressure formula (BP = CO × TPR), the CO determinant is affected by
blood volume. AII hormone indirectly has a crucial role in maintaining the blood
volume. This is via the control of sodium balance by its action on stimulating the
secretion of the adrenal cortical hormone aldosterone (note the adrenal
medullary catecholamines that have effects on blood pressure are stimulated by
sympathetic nerves). Sodium balance is the main determinant of extracellular
fluid (ECF)/blood volume. In addition, the AII has been shown to be a
dipsogenic (increases thirst/water intake) and stimulated vasopressin release
from the posterior pituitary. The use of ACE inhibitors in prescription for
hypertension is well known. The kidneys are the source of the enzyme/hormone
hypertension is well known. The kidneys are the source of the enzyme/hormone
renin that cleaves a plasma protein, angiotensinogen to generate the AII
precursor AI. AII itself has a direct effect in increasing the sodium reabsorption
from the proximal tubule of the nephron. By its constricting action on the renal
arterioles, the AII also conserves sodium by reducing the glomerular filtration
rate (GFR) and thus the filtered sodium load. So, we have here an integrated
picture of the lungs and the kidneys collaborating with the heart/blood vessels to
regulate blood pressure.
It makes physiologic sense, that the lungs have a role in ensuring a normal
arterial blood pressure. Oxygenated blood must circulate adequately to the
tissues to be useful. Sluggish blood flow, e.g., during cardiac failure, results in a
stagnant hypoxia. The driving pressure for tissue perfusion is the mean arterial
pressure.
8. How does an alveolar dead space and anatomical dead space compare in terms
of its CO2?
Answer
All “dead” spaces in pulmonary physiology are sites of nonexchange. Therefore,
the air in “dead” spaces, whether anatomical or alveolar will resemble inspired
air and the partial pressure of CO2 will be close to 0 mmHg.
Concept
Students are often “dead” confused with the terminology of some respiratory
terms and one in particular is “dead” space. It is helpful to think of “dead” space
as a location, where there are no exchange respiratory gases. This means that the
partial pressures of gases in the inspired air at these places remain unaltered.
The reason for the nonexchange in anatomical and alveolar “dead” spaces
are slightly different. All normal, living persons have anatomical “dead” space
(ADS)! This is the space or anatomical volume in the airways of the respiratory
tree that functions as conduits for airflow to the respiratory exchange alveoli
region. Each tidal volume during expiration, thus, comprises a mixture of
alveolar air and unexchanged air in the ADS. This explains why expired PCO2 is
lower than alveolar air PCO2 (< 40 mmHg). It also accounts for the fact that
expired air PO2 is higher than alveolar air PO2 (> 103 mmHg).
An alveolar “dead” space is not a normal situation. All alveoli should be
involved in gas exchange. If a local region of the lungs is deprived of blood flow
(e.g., pulmonary embolism), then the air of the ventilated alveoli in that
nonperfused region will remain unchanged. In terms of ventilation/perfusion
nonperfused region will remain unchanged. In terms of ventilation/perfusion
ratio, the V/Q has a ratio of infinity. I help students to remember the “dead”
space V/Q by linking “infinity” with outer (“dead”) space!
9. How might you expect the FRC and the total lung capacity (TLC) to change
when standing up from lying down?
Answer
The TLC remains the same while the FRC is less in the supine compared to the
upright position.
Concept
The TLC is the lung volume that is achieved with a maximal inspiratory effort.
This maximally filled lung volume should be the same in a normal person, lying
or standing up. The FRC volume is that at the end of a normal expiration. This
volume is determined by two opposite recoil forces, namely the inward recoil of
the lungs and the outward recoil of the chest wall. The chest wall and diaphragm
is functionally considered as a single mechanical unit. When lying down, there is
some compression of the diaphragm by the abdominal contents (more when a
person is fat!). This means that the outward recoil of the diaphragm/chest wall is
decreased. The balance of the lung/chest wall recoil will now shift to a decreased
FRC. Since the TLC is unchanged in either posture, the inspiratory capacity is
actually more in the supine position. This may sound unusual to the student since
the word “capacity” by instinct seems naturally to be better in the standing
person.
Clinically, an enlarged abnormal FRC is seen is emphysema. This
obstructive lung disease is associated with a loss of elastic lung tissues. The
inward elastic lung recoil is thus reduced. The balance of lung/chest wall recoil
is pushed outwards to a bigger FRC. The phenomenon of “air-trapping” due to
the increased airway resistance in emphysema also contributes to the larger FRC.
Regional, less than optimal ventilation or blood perfusion is compensated by a corresponding reduction in
the paired perfusion or ventilation respectively. This is to match the ventilation/perfusion balance, to lessen
“wasted”, “overperfused” alveolar blood flow or “overventilated” alveoli
10. In an asthmatic attack, why does sitting up from lying in bed help to relieve
the breathing difficulty?
Answer
The lung compliance is higher in the upright lung since the alveoli are expanding
against a significant larger pulmonary blood volume in the supine position
(dense mesh of capillary network at each alveolus)
Concept
In a normal person, the slight difference in lung compliance between lying and
standing is of little consequence (all students find the horizontal position
comfortable!). During labored breathing in asthmatics due to increased airway
resistance (hyperresponsive airways in asthma produce the bronchoconstriction),
any change in body position that helps ease the dyspnea will be assumed by the
person. There is a significant more pulmonary blood volume in the supine
position compared to the upright lungs as the pulmonary vasculature being
relatively compliant. When sitting up, the asthmatic lungs have an improved
compliance as the alveoli are expanded against a decreased “sheath” of
pulmonary blood that surrounds the alveoli.
In the normal lungs, the lung compliance changes with the lung volume.
Lung compliance is less at very small volumes near the residual volume. Lung
compliance is also decreased near the maximal total lung capacity. Thus, the
lung compliance curve (lung volume versus transpulmonary pressure) is a
sigmoid with lower compliance at low and high lung volumes. A useful
sigmoid with lower compliance at low and high lung volumes. A useful
demonstration of this volume/compliance relationship is the action of blowing a
balloon. It takes more effort to blow up the balloon at the beginning. The
midway expansion of the balloon is easier, and as the balloon reaches near its
maximal size, increased blowing pressure is again needed.
© Springer International Publishing Switzerland 2015
Hwee Ming Cheng, Physiology Question-Based Learning, DOI 10.1007/978-3-319-12790-3_8
8. Oxygen Respiratory Physiology
Hwee Ming Cheng1
(1) Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
Hwee Ming Cheng Email: chenghm@ummc.edu.my
It is good to distinguish between the term “ventilation” and “oxygenation.” If
one notes the different units for ventilation (ml Air/min) and oxygenation (ml
O2/min), it becomes obvious that they have quite different meanings. Airflow is
dependent on the difference in air pressure. Oxygenation, however, is by simple
diffusion and depends on the availability of a partial pressure gradient for
oxygen (PO2). In the liquid blood medium, the PO2 refers only to the dissolved
portion of oxygen in plasma/cytosol.
1. How is the change present in the fractional concentration of oxygen with
increasing altitude?
Answer
There is no change in the fractional concentration, but there is a decreasing PO2
with increasing altitude.
Concept
The partial pressure of oxygen is calculated by multiplying the fractional
concentration with the atmospheric pressure. At sea level, the oxygen comprises
21 % of air composition. Thus, the partial pressure of oxygen is
0.21 × 760 mmHg which gives ~ 160 mmHg.
The atmospheric pressure decreases with ascent to higher altitude, but the
fractional concentration of oxygen is unchanged. At the atmospheric pressure of
500 mmHg, the partial pressure will drop to 0.21 × 500 or 105 mmHg.
There is a gradient of PO2 from dry inspired air to the alveolar air, from
160 mmHg to 103 mmHg. If the starting inspired air has a reduced PO2 of
105 mmHg, the alveolar air PO2 will decrease in parallel. This hypoxia with a
low arterial blood PO2 (hypoxic hypoxia) is due to the fall in atmospheric air
PO2.
At sea level, the theoretical maximum the PO2 in alveolar air can reach is
~ 160 mmHg with voluntary hyperventilation. With normal breathing at rest, the
arterial blood PO2 at 100 mmHg has a hemoglobin (Hb)-O2 saturation of
~ 98 %. Thus, a voluntary effort in breathing by increasing the alveolar air PO2
will not dramatically increase the total blood oxygen content.
A different situation, where the alveolar air PO2 might become 160 mmHg,
is a nonperfused alveolus. Since oxygen is not extracted with the absence of
blood supply to the alveolus, the alveolar air PO2 is unchanged at ~ 160 mmHg.
Of course, the high PO2 is the wasted ventilation to the nonperfused alveolus.
The alveolar PO2 is an equilibrium value between fresh input of tidal volume air and extraction of O2 into
pulmonary capillary blood. The expired tidal volume (TV) actually has a higher PO2 than alveolar air since
the expired TV is a mixture of alveolar air and unaltered, inspired air in the anatomical dead space
2. How is the value of partial pressure of oxygen in anatomical dead space
calculated at normal body temperature?
Answer
The partial pressure is calculated by multiplying the fractional concentration of
oxygen with the pressure (atmospheric minus the water vapor pressure at 37 °C)
Concept
Concept
Inspired air is very soon moistured within the respiratory tree. The water vapour
pressure is dependent on the temperature. At 37 °C, it is 47 mmHg. Thus, the
partial pressure of oxygen in the warmed, moisture air will be 0.12 (760–47) or
~ 150 mmHg. The anatomical dead space contains air that will not be altered as
there is no exchange of the respiratory gases.
In the alveolar gas equation, the inspired PO2 is used to calculate the alveolar
air PO2 in this equation: Alveolar PO2 = Inspired PO2− alveolar PCO2/R, where
R is the respiratory exchange ratio or respiratory quotient (rate of CO2
production/rate of oxygen consumption) Normally R = 0.8 and putting in values,
Alveolar PO2 = 150 mmHg (see Q1) minus 40/0.8, giving alveolar PO2 as
100 mmHg.
Graphically in physiology texts, the relationship between alveolar air PCO2
and PO2 described by the alveolar gas equation is shown as the CO2 (y-axis)–O2
(x-axis) diagram. The relationship is an inverse one ranging from a value similar
to mixed venous blood (PCO2 46, PO2 40 mmHg in a nonventilated alveolus) to
inspired air (PCO2 0, PO2 100 mmHg, in a nonperfused alveolus).
3. How does the PO2 change in its value along the pulmonary capillary blood?
Answer
The PO2 in the pulmonary capillary exposed to alveolar air rises from 40 mmHg
to 103 mmHg.
Concept
Deoxygenated blood in pulmonary arterial blood is pumped by the right
ventricles to the lungs. This mixed venous blood has a PO2 of 40 mmHg and the
hemoglobin is 75 % saturated with oxygen. At the alveolar capillaries, rapid
equilibration takes place and the blood PO2 increases to reach 103 mmHg, the
PO2 in alveolar air. This net diffusion of oxygen down the PO2 gradient across
the alveolar capillary membrane is completed in half of the alveolar capillary
blood transit time.
In the diffusion capacity of oxygen in the lungs (DLO2 ~ VO2/PO2 gradient),
the partial pressure denominator is the difference between alveolar air PO2 and
the Mean alveolar capillary PO2. The Mean value is used because the PO2
gradient progressively decreases along the alveolar capillary.
The diffusion capacity of oxygen in the lungs (D L O 2 ) across the alveolar-capillary (a/c) membrane is the
rate of oxygen diffusion per mmHg O2 partial pressure difference across the membrane. Note that the
pulmonary alveolar capillary PO2 progressively increases along the capillary. Total available surface area
of the a/c membrane is also a major factor in passive O2 diffusion
The value for alveolar PO2 at 103 mmHg in reality also represents an
average alveolus in the whole lungs. When we consider the upright lungs and the
normal ventilation/perfusion difference, the actual value of the alveolar air PO2
is more than 103 mmHg in the apex and less than 103 mmHg at the basal alveoli
(note this is not the same as alveolar ventilation being better at the basal alveoli
and oxygenation also better at the base of the lungs).
The blood that leaves the lungs in the pulmonary vein represents the sum of
blood from all regional alveoli in the upright lungs and has an average arterial
blood PO2 of 100 mmHg (and arterial PCO2 of 40 mmHg). Thus, the alveolar air
PO2 of 103 mmHg might be viewed as in a representative alveolus in the supine
person when gravity does not produce the varied ventilation/perfusion (V/Q)
distribution across the upright lungs. PO2 of 103 mmHg is that of air in the
resting “horizontal” alveoli.
4. What does “perfusion-limited” diffusion of oxygen mean at the alveolar
capillary membrane?
Answer
Since rapid equilibration of PO2 occurs at the alveolar capillary, further
oxygenation is possible only if the flow of deoxgenated blood into the lungs
increases.
Concept
Diffusion of respiratory gases occurs by simple diffusion, and net diffusion
continues down the partial pressure gradient until the partial pressure equalizes.
In normal lungs, the exposure time of deoxygenated blood to the alveolar air is
less than one second. Rapid equilibration of PO2 is achieved in less than 0.5 s.
Beyond the point of PO2 equilibrium at 103 mmHg, there is no further diffusion
and thus no further oxygenation.
In pulmonary disease with “alveolar-capillary block,” the diffusion distance
is increased due to thickening of the alveolar capillary membrane. If the
reduction of diffusion is severe, equilibration of PO2 is not reached. The
pulmonary capillary blood PO2 remains less than 103 mmHg; the lower the
value, the greater the restriction in oxygen diffusion. This situation is also called
“diffusion limited.”
The perfusion-limited oxygenation in the lungs at rest is overcome during
exercise with a greater pulmonary blood flow when the right ventricle supplies a
bigger cardiac output.
In a similar way, the unloading of oxygen at the tissues can also be said to be
“perfusion limited.” At the cells, oxygen is extracted from arterial blood in the
capillary as oxygen diffuses rapidly down its partial pressure gradient
(100/40 mmHg). When the capillary blood near the venous end is reduced to
40 mmHg, no further unloading of O2 occurs if we take the tissue PO2 at
40 mmHg. In order for more delivery and release of oxygen from blood to the
cells, a greater flow of oxygenated blood into the microcirculation must occur.
The increased skeletal muscle blood flow during exercise fulfills this
function. This “perfusion-limited” diffusion of oxygen at the tissues also
explains why in sluggish tissue blood flow (e.g., in cardiac failure or blocked
regional blood vessel), the cells do not extract more oxygen. In fact, the cells are
deprived of sufficient oxygen is what is known as stagnant hypoxia.
5. What accounts for the normal difference in PO2 in alveolar air and arterial
blood?
Answer
The physiological shunt for oxygen is due to a little mixing of deoxygenated
blood from the cardiac veins and bronchial circulation.
Concept
The alveolar capillary blood equilibrates with the oxygen rich alveolar air at PO2
of 103 mmHg. The value of PO2 in arterial blood is normally slightly lower at
around 97 mmHg. This normal decrease from alveolar air to arterial blood is
called physiological shunt. The accepted difference in this A-a PO2 should not
be greater than 15 mmHg.
The total oxygen content in blood is the sum of the dissolved O2 and the hemoglobin-bound O2. The
dissolved O2 is determined by the partial pressure of O2. The dissolved O2 is in equilibrium with and
determines the amount or saturation of hemoglobin-bound O2
The reason for the physiologic shunt is due to anatomical reasons. Some of
the bronchial blood flow does not get reoxygenated and mixes with oxygen-rich
blood draining from the lungs. In addition, some coronary venous blood also
enters directly into the left ventricles.
If there is an anatomical defect producing, in this case an abnormal
anatomical shunt, then the alveolar-arterial PO2 will be increased. This occurs,
e.g., in an atrial septal defect resulting in what is called a right to left shunt. A
portion of the dexyogenated blood in the right atria is shunted into the left atria
and dilutes the PO2 of the oxygenated blood that is pumped out via the aorta and
arteries.
Shunting of blood can also happen within the lungs in intrapulmonary shunt.
The alveoli at intrapulmonary shunt are not well ventilated (the
ventilation/perfusion ratio will be reduced). The pulmonary blood draining these
underventilated alveoli (e.g., when a branch of the respiratory tract is blocked)
will have decreased PO2. This underoxygenated blood will then mix with blood
from normal ventilated alveoli. The arterial blood PO2 will thus be depressed,
and the A-a PO2 difference widens.
6. State the axes in the oxyhemoglobin dissociation graph.
6. State the axes in the oxyhemoglobin dissociation graph.
Answer
The x-axis is the partial pressure of oxygen in mmHg and the y-axis is the
hemoglobin saturation in percentage.
Concept
The x-axis is the variable or we could say the “cause” and the y-axis is the effect
of changing the x values. Relationships are expressed and specified by x-y
values. In the oxyhemoglobin dissociation graph (not wrong to call it association
graph actually!), the key point is that the percentage Hb-O2 saturation is
dependent on the PO2. Increasing PO2 will give a higher HB-O2 saturation.
The PO2 is the dissolved oxygen and this dissolved O2 is in equilibrium with
the hemoglobin-bound O2. It is important to understand that the PO2 determines
the Hb-O2 saturation, but the reverse is not correct. The amount of oxygen bound
to Hb does not affect the PO2. Note that at arterial blood PO2 of ~ 100 mmHg,
the HB-O2 saturation is already ~ 98 %. At venous and tissue PO2 of 40 mmHg,
the Hb-O2 saturation does not drop to 40 % but is still at 75 %. This indicates
that there is still a large reserve oxygen content in venous blood.
Playing cards can be used to review and enjoy respiratoy physiology. There are several numbers in
respiratory function to note. Here, the students will recognize that the PO2 103–PO2 97 mmHg represent
the normal, physiologic shunt which is due to normal anatomical architecture. A little deoxygenated blood
in certain bronchial and cardiac blood vessels minimally dilutes the oxygenation in the systemic arterial
blood
The Hb-O2 curve is not a linear line but shows a sigmoid shape due to the
unique cooperative binding reaction between hemoglobin and O2. One cellular
benefit of this is that at the PO2 of 60 mmHg (a big decrease of 40 mmHg from
normal arterial PO2), the Hb-O2 saturation is still at ~ 90 %. This providential
coincidence allows mountain climbers to enjoy their high altitude adventures.
The student should note that the steep portion of the Hb-O2 curve is around
PO2 of 40 mmHg. This is the operating PO2 region at the tissues and thus an
advantageous characteristic of the Hb-O2 interactions. At the tissues, small
changes in PO2 will produce a greater change in the Hb-O2 saturation. In other
words, the unloading of oxygen to the cells, if the PO2 decreases a small amount
to 38 mmHg, is significant.
Blood oxygen bound to hemoglobin is around 98 % of the total blood O2
content, with a small percentage dissolved in blood. Therefore, if the y-axis is
changed to the blood oxygen content (ml O2/dl blood), the shape of the Hb-O2
graph will remain identical. In iron-deficiency anemia, the total blood oxygen
content will be reduced. But, since the hemoglobin is normal, the Hb-O2
saturation at any given PO2 will not be altered in this type of anemia.
7. State Bohr’s effect in the lungs.
Answer
In the lungs, the lower partial pressure of CO2 increases the hemoglobin affinity
for oxygen and enhances the uptake of oxygen from alveolar air into pulmonary
capillary blood.
Concept
The Bohr’s effect explains how the partial pressure of CO2 affects the blood
oxygen content. A higher PCO2 (> 40 mmHg) decreases the Hb-O2 affinity. This
occurs in the tissues where the local PCO2 is 46 mmHg. More unloading of
oxygen from the arterial blood is promoted and the blood oxygen content is
reduced.
Conversely, when the blood is reoxygenated in the lungs, the PCO2 returns
to 40 mmHg. The Hb-O2 affinity becomes higher again to ease the oxygenation
of blood in the lungs. Bohr’s effect is also accounted for by changes in pH. The
metabolically active cells have a local pH of less than 7.4. A decrease in
pH < 7.4 also reduces the Hb-O2 affinity. This makes physiologic sense since
more oxygen will be released from Hb to the cells in the environment of lower
pH. Thus, protons and CO2 have the same triangle relationship with hemoglobin.
One can view deoxygenated Hb as having more affinity for H+ and CO2, which
accounts for Haldane’s effect(or oxyhemoglobin binds less to CO2/H+). From the
perspective of Mr. Bohr, both CO2 and H+ binding to hemoglobin reduces the
affinity of Hb for oxygen and unloads more oxygen to the cells. The student
could draw a creative cartoon of Mr. Bohr and Mr. Haldane travelling in the red
capsule and discussing or arguing about whose effects comes first!
The student should be careful to use oxygen language specifically. Changes
in partial pressure of O2 do not affect the Hb-O2 affinity. It is the Hb-O2
saturation which is determined by the PO2 not the affinity of Hb for O2. But,
factors other than PO2 (which is the variable along the x-axis of Hb-O2
dissociation curve) affect the Hb-O2 interactions.
For Bohr’s effect, changes in PCO2 and pH alter the interactions or affinity
between Hb and oxygen.
8. What does the 50 in the P50 oxyhemoglobin index indicate?
Answer
The 50 means 50 % Hb-O2 saturation. The P50 is the partial pressure of O2 that
is required to give a 50 % Hb-O2 saturation.
Concept
In oxygen transport language, the P50 index is an indicator of the Hb-O2 affinity.
If the partial pressure needed to achieve 50 % Hb-O2 saturation is higher, this
mean that the hemoglobin has a reduced affinity for O2. If you need more effort
or pressure to make two persons like each other, then the natural chemistry
between them must be low!
Normally, the P50 index has a value of 27 mmHg. At 27 mmHg, there will be
a 50 % Hb-O2 saturation. This P50 value is defined at certain set conditions. The
conditions are body temperature 37 °C, blood pH 7.4, and blood PCO2
40 mmHg. These are the conditions of arterial blood. Implied is that changes in
body temperature, blood pH, or PCO2 will change the P50 meaning, and they will
change the affinity of hemoglobin for O2.
If we look at the Hb-O2 dissociation graph, if the P50 is increased
> 27 mmHg, there would be a shift of the curve to the right. A decreased P50 of
less than 27 mmHg will shift the curve to the left.
We can now combine three different ways of talking about changes in Hb-O2
affinity. An increased affinity will have a lower P50 associated with aleftward
shift of the Hb-O2 curve.
Conversely, a decreased affinity will increase the P50 and shift the Hb-O2
curve to the right.
Oxygen transport and delivery must be appreciated from the cell perspective.
Yes, the tissues are “cellfish” and are only satisfied when they have their oxygen
needs met. A decreased Hb-O2 affinity benefits the cell since more oxygen is
unloaded to them. Think of the rightward shift of the HB-O2 curve as releasing
more O2 to the cells. You give with your generous right hand!
9. What two factors affect the change in P50 during physical activity?
Answer
An increased tissue PCO2 and decreased pH increase the P50, thus favoring the
unloading of oxygen to the cells by decreasing the Hb-O2 affinity.
Concept
The body is well designed to serve its own diverse functions. During exercise,
the blood flow to skeletal muscle increases as a result of increased cardiac output
and local arteriolar vasodilatation in the muscles.
The oxygen diffusion at the microcirculation is also higher since the partial
pressure gradient is greater. This PO2 gradient is not due to any increase in
arterial PO2 (in moderate exercise, the PO2 is unchanged). It is rather the
decreased tissue PO2 < 40 mmHg as a result of more cellular usage of oxygen.
The surface area for diffusion is also increased by the vasodilation. Vasodilation
also has the effect of decreasing the diffusion distance if some capillaries that are
not so patent at rest are recruited during muscle activity.
In addition, the local conditions of more active cells all have the effects of
promoting more unloading of O2 from capillary blood. This is a most wonderful,
appropriate physiologic arrangement in response to the need for more O2. The
three conditions—local PCO2 (at 46 mmHg or higher), lower pH as well as
warmer tissues during physical activity all loosen the affinity of Hb for O2.
At rest, the tissue extraction of oxygen is about 25 %. This means that the
total blood oxygen content is reduced by a quarter, from arterial 20 ml to 15 ml
oxygen percentage. Since most of oxygen content in blood is hemoglobin bound,
the percentage saturation of Hb-O2 also decreases by about 25 %, from ~ 98 to
75 % (PO2 at 40 mmHg). The normal consumption of oxygen is calculated by
multiplying the cardiac output (5000 ml/min) with the tissue extraction of 5 ml
O2/100 ml of blood. This gives a value of 250 ml O2/min.
During muscle activity, the venous blood PO2 can be less than 40 mmHg.
This means the Hb-O2 saturation in venous blood will also be less than 75 %.
10. How does the change in P50 during carbon monoxide overdose worsen its
toxicity?
Answer
Carbon monoxide toxicity makes the hemoglobin bind to oxygen more tightly
(reduced P50) and prevents oxygen unloading to the hypoxic cells.
Concept
Hemoglobin has a 200 fold greater affinity for carbon monoxide (CO) compared
to for oxygen. Thus, the blood oxygen content is drastically reduced in CO
poisoning. Because CO has no smell, this makes it particularly dangerous as the
presence of the gas is not noticed. The CO in blood does not affect the dissolved
oxygen and the PO2 is unchanged. The arterial chemoreceptors are, thus, not
stimulated, and there is no increased breathing to indicate the infiltration of CO
into the body. Perhaps, this is why CO inhalation is a common method of choice
for persons who decided to end their lives in a relatively comfortable way.
In addition, the remaining oxygen in the Hb-CO saturated blood is less
readily released to the tissues. This is due to an unusual change in the Hb-CO
that increases the affinity of Hb for oxygen. This increased Hb-O2 affinity is
pointless in CO toxicity, when the most of the hemoglobin is occupied with CO
instead of O2. The situation is worsened since the remaining oxygen cannot be
easily unloaded to the hypoxic cells in this severe category of anemic hypoxia.
The CO-Hb–O2 curve shows a shift to the left.
In a different situation that occurs at extreme high altitude, the respiratory
alkalosis has a compensatory effect in increasing Hb-O2 affinity. As the very low
partial pressure of oxygen in the thin atmospheric air at the high altitude, this
increased affinity helps the climber to improve the lung oxygenation. This is
seen as a decreased P50 with a left shift of the Hb-O2 curve.
At moderate altitudes, the rise in erythrocyte 2, 3 diphosphoglycerate (DPG)
due to altitude hypoxia normally decreases the Hb-O2 affinity (right shift of HbO2 curve) to compensate and improve cell O2 supply.
© Springer International Publishing Switzerland 2015
Hwee Ming Cheng, Physiology Question-Based Learning, DOI 10.1007/978-3-319-12790-3_9
9. CO2 Respiratory Physiology
Hwee Ming Cheng1
(1) Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
Hwee Ming Cheng Email: chenghm@ummc.edu.my
Carbon dioxide is generally viewed as a metabolic gaseous waste product. It is a
major byproduct of cellular metabolism of energy substrate in our foods,
including carbohydrates, fats, and proteins. The lungs are the site of elimination
of CO2, expired in our breath. Above this metabolic picture, the student should
remember that CO2 and its associated carbonic acid is a determinant of blood
pH. In other words, pulmonary function is tightly linked to the homeostatic
control of blood pH. In addition, the metabolite CO2 is a vasodilator which
regulates regional blood flow.
1. What is the major form of carbon dioxide transported in arterial blood?
Answer
The partial pressure of CO2 in arterial blood is 40 mmHg and in venous blood is
46 mmHg. In terms of blood content, the arterial CO2 content is 48 ml
CO2/deciliter and 52 ml CO2/dl in venous blood at rest. This means that for
every 100 ml of pulmonary blood flow that passes the lungs, 4 ml of the 52 ml
CO2 is expired. With a resting cardiac output of 5 L/min, the rate of CO2
released in the lungs is 200 ml/min of CO2.
Arterial blood CO2 content (CaCO2) is distributed as three forms. Around two thirds are transported as
converted CO2, plasma bicarbonate. Smaller amounts are carried as carbamino-hemoglobin (Hb-CO2) and
as dissolved in blood. Hb also buffers the hydrogen ions generated from hydration of CO2 by the red cell
enzyme, carbonic anhydrase
In both venous and arterial blood, CO2 is transported in three major forms. A
small percentage of CO2 is dissolved in plasma and cytosol of red cells. A
slightly larger portion is bound to hemoglobin to form carbamino-hemoglobin.
The largest fraction (~ 70 %) of blood CO2 content is in the form of plasma
bicarbonate anion, HCO3. Bicarbonate is formed from carbonic acid which is
generated within the erythrocytes by hydration of CO2. At the tissues, the CO2
diffuses easily into the blood and into red cells down its partial pressure gradient.
Thus, hemoglobin in red cells has three physiologic roles; besides the wellknown fact of binding oxygen, hemoglobin also combines with CO2 to form
carbamino-Hb, and Hb is also an important blood buffer for pH control. Note
that the three forms of CO2 transported in blood are in equilibrium with each
other; the dissolved, the Hb-bound and the plasma bicarbonate.
2. What enzyme function in red blood cells is essential for CO2 transport?
Answer
The erythrocyte has the enzyme carbonic anhydrase that converts CO2 to
carbonic acid, which then dissociates into the anion bicarbonate and hydrogen
ion.
Concept
The red cells are essential in transporting CO2 in blood, besides carrying oxygen.
The red cells contain the enzyme carbonic anhydrase C@ which is needed for
the hydration of CO2 inside the red cells. The subsequent carbonic acid
dissociation is the source of the major form of total CO2 transported in the blood
(bicarbonate anions). The reaction of carbon dioxide with water by C@ is a
reversible reaction:
. The reaction is driven to
the right at the tissues. In the lungs, a reversal of the kinetics favors a leftward
reaction with the release of CO2 from the pulmonary capillary blood into the
alveoli.
There are three other organs, in which the carbonic anhydrase enzyme plays
a central role. The parietal cell of the stomach secretes hydrochloric acid. The
proton that is secreted is generated inside the gastric parietal cells, catalyzed by a
C@. In the pancreas, the ductal cells secrete bicarbonate which is a major
component of pancreatic excocrine secretion. The ductal cells produce the
bicarbonate by an action of C@ in the ductal cells. In the kidneys, both the
reabsorption of filtered bicarbonate, tubular synthesis of bicarbonate, and tubular
secretion of protons are effected by C@ present in the epithelial cells of specific
nephron segments.
3. How is hemoglobin buffering action involved in CO2 transport?
Answer
Hemoglobin is an important blood buffer, an intracellular buffer circulating
inside red blood cells! There are two reactions involving hemoglobin including
the buffering action that enables the blood to carry excess CO2 from the tissues
to the lungs. The hemoglobin forms carbamino-Hb with CO2 (do not confuse
this Hb complex with a similar sounding carboxy-Hb which is formed during
carbon monoxide toxicity).
Carbonic acid is generated inside red cells by the catalytic action of carbonic
anhydrase. The dissociation of carbonic acid into bicarbonate and proton is
enhanced by the buffering action of hemoglobin. By buffering H+, the
dissociation is promoted and more bicarbonate is produced. Bicarbonate, then, is
exchanged at the red cell membrane for chloride and the increased biacarbonate
concentration in venous blood represents the major form of CO2 content in
venous blood.
This bicarbonate/chloride interchange is reversed at the alveolar capillary,
where the reaction is pushed towards release of gaseous CO2 into the lungs. The
red cell membrane chloride shift event has been called “Hamburger” effect, after
the Dutch physiologist Hartog Jakob Hamburger.
4. State the effect of Haldane’s effect at the muscle tissue during physical
activity?
Answer
Decreased partial pressure of oxygen at the exercising muscles will favour the
uptake of carbon dioxide into the capillary blood.
Concept
Haldane’s effect describes how changes in the partial pressure of oxygen will
affect the CO2-carrying capacity of blood. Increased PO2 will lower and
decreased PO2 will raise blood CO2 content. This inverse relation between PO2
and blood CO2 content named Haldane’s effect is obviously advantageous and
physiological. At the lungs when blood becomes oxygenated and PO2 increase
from 40 to 100 mmHg, the blood “holds” less CO2 and this favours CO2
elimination at the lungs. At the tissues, when oxygen is extracted from the blood,
the deoxygenated blood with lower PO2 (from 100 to 40 mmHg) will have a
greater capacity to take up metabolic CO2 from the cells.
The mechanism for Haldane’s effect can be biochemically explained.
Deoxygenated Hb has a higher affinity for CO2 and hydrogen ions. Thus, more
carbamino-Hb is formed. The greater buffering of H+ will also promote more
CO2 transport in the form of the major species, bicarbonate ions (see Q3 above).
Carbon dioxide exchange at the cells and the lungs are dependent on the CO2 partial pressure gradient at
the metabolic and ventilatory sites, respectively. The concurrent change in the oxygen partial pressures at
the cells or tissues also promote CO2 extraction from tissues and CO2 removal from pulmonary blood
(Haldane’s effect). The partial pressure of CO2 is in chemical equilibrium with the hemoglobin-bound
CO2/H+ and with plasma bicarbonate anions
The student must not have the mental picture that CO2 will replace all the
oxygen on hemoglobin. The venous deoxygenated Hb is still 75 % saturated
with oxygen at rest. Thus, the carbamino-Hb and oxy-Hb coexist on the same
carrier molecule. Similarly at the lungs, it should not be imagined that the
oxygenation of blood will displace all the CO2 from hemoglobin. In arterial
blood, PCO2 has a value of 40 mmHg, just 6 mmHg lower than in mixed, venous
blood. The arterial blood CO2 content has all three forms of CO2—the
bicarbonate, the carbamino-Hb, and dissolved CO2.
You might say that CO2 and O2 have a love –“Hbate” relationship. The two
respiratory gases are together on the hemoglobin molecule, and they also nudge
each other away at specific places and at times of their life journey together!
The red cell protein, hemoglobin has three carrier functions. Oxy-hemoglobin represents at least 99 % of
blood oxygen content. Carbamino-Hb is a small component of blood CO2 content. Hemoglobin is also an
essential blood buffer, and this role of Hb prevents venous blood pH from becoming acidic. The buffering
action of Hb for hydrogen protons also enhances the formation of bicarbonate anions as the major form of
blood CO2 content. Hb also carries nitric oxide (NO). DeoxyHb has less affinity for NO, so at the tissues
NO is released to produce vasodilation
5. What are the parameters of the y- and x-axes of the CO2 transport curve?
Answer
The x-axis is partial pressure of CO2 and the y-axis is the blood oxygen content.
Concept
A graphical illustration of physiological relationships is helpful, and they not just
show a single situation cause and effect (c & e) but a range of varying situations.
Generally, a considerable number of students in a class will be averse to graphs.
I call this “graph’s disease/syndrome”!
I call this “graph’s disease/syndrome”!
By noting carefully the specific parameters of the axes, the student can
become more versatile with understanding physiology in changing situations. In
the CO2 transport curve, the x-axis is the partial pressure of CO2 and the
physiologic range of interest is normally shown in textbook as 30 to 50 mmHg.
This range will include the 40–46 mmHg fluctuations for CO2 in arterial-venous
blood. Note that there is no subscript after the P for CO2 in the axis. The y-axis
is the blood CO2 content expressed as milliliter CO2/100 ml of blood. The y
values shown in CO2 transport graph are normally 40–60 as this will include the
48–52 ml CO2/dl in arterial and venous blood, respectively.
There will always be two curves in the CO2 transport graph. This is because
the CO2 content is affected by ongoing changes in the partial pressure of oxygen.
If PO2 is not considered, we only look at one of the curve. For example, the
upper curve is given for when PO2 is 40 mmHg (deoxygenated venous blood).
This curve shows increasing CO2 content with increasing PCO2. A difference
with the hemoglobin-oxygen transport curve is that there is no apparent plateau
phase as in the case with Hb-O2 when hemoglobin near saturation is reached.
In reality, at the lungs when PCO2 decreases from 46 to 40 mmHg, the
partial pressure for oxygen does not remain at 40 mmHg, but the lung
oxygenation rapidly arterialized the blood to PO2 ~ 100 mmHg. Thus, when
following the events for CO2 transport from tissues to the lungs, we have to
change the curve from the upper one to the lower one where PO2 has become
100 mmHg. Looking at the point of intersection at PCO2 40 mmHg (x-value) for
the two curves, it is clear that the CO2 content (y values) is reduced more for the
lower curve of oxygenated blood at PO2 100 mmHg.
The presence of the two curves is a demonstration of the Haldane’s effect.
Haldane’s effect is the effect of PO2 on blood CO2 content. This is described as
a shift of the CO2 transport curve to the right with higher PO2, i.e., at any given
PCO2, oxygenation (at the lungs) will further decrease the CO2-carrying capacity
of blood and reduce its CO2 content.
6. How is the pH of venous blood related to the concentration of bicarbonate?
Answer
The pH of venous blood is dependent on the ratio of bicarbonate to the carbonic
acid concentration.
Concept
There are several chemical buffers in the extracellular fluid (ECF) which
includes the blood volume. These chemical buffers provide the first line of
defence against a pH threat. The main chemical buffer in the ECF is the
bicarbonate/carbonic acid buffer. At any pH, the base and acid components of all
the different chemical buffers are linked to each of the other chemical buffers by
the same pH (isohydric principle). We need only, therefore, to monitor the
bicarbonate and carbonic acid concentrations to ascertain the pH landscape. The
carbonic acid concentration is determined by the partial pressure of CO2 and at
the normal arterial blood PCO2 of 40 mmHg, and pH of 7.4, the carbonic acid
concentration is 1.2 mmol (a conversion factor of 0.3).
Normal bicarbonate concentration is arterial blood is 24 mmol/L. The ratio is
then 20 at the pH of 7.4. The bicarbonate/PCO2 buffer system is the main buffer
as the buffer pair is an “open” system. The “open” term indicate that the
amount/concentration of the HCO3 and PCO2 is not limited. Both the base and
acid components are “open” to be increased or decreased in compensatory
response to pH changes. The bicarbonate is “open” to be modified by the renal
function and the PCO2 is “open” to the respiratory function. An elegant
relationship for this “open” concept of pH control by two major organs acting
via the HCO3/PCO2 is
The venous pH is slightly acidic due to the effective buffering of protons by
hemoglobin. The venous bicarbonate base concentration is higher than that in
arterial blood since a large fraction of metabolic CO2 has been transformed to
the anion. However, the venous pH is not due to the absolute concentration of
bicarbonate but to the ratio of HCO3 to PCO2. The PCO2 in venous blood is
46 mmHg, up from 40 mmHg in arterial blood.
7. How are the three parameters of alveolar ventilation equation related?
Answer
The partial pressure of CO2 in alveolar air (PACO2) is related to the ratio of the
rate of CO2 production (VCO2) to the alveolar ventilation (VA).
Concept
At rest, if the rate of CO2 production is unchanged, the PCO2 is inversely related
to the rate of alveolar ventilation. If this is plotted on a graph, there is a
hyperbolic inverse relationship between alveolar ventilation (x-axis) and alveolar
PCO2 (y-axis). The value of resting alveolar ventilation should then fall on the
graph at PCO2 of 40 mmHg. If a person voluntarily hyperventilates, the alveolar
PCO2 will decrease. Since arterial blood PCO2 is the same as alveolar air PCO2,
the blood will be hypocapnic, and the condition is also called respiratory
alkalosis since hypocapnia will increase the blood pH.
What will happen if the rate of CO2 production is increased? How will the
relationship between alveolar ventilation and alveolar PCO2 change? The basic
hyperbolic, inverse relationship between the ventilation/PCO2 will remain the
same. However, for the alveolar air PCO2 to remain at 40 mmHg (y-axis) at the
greater rate of metabolic CO2 release from cells, the alveolar ventilation has to
increase (y-axis). Thus, the hyperbolic curve shifts to the right with a higher
cellular CO2 generation.
This is a useful place to consider cause and effect (c and e) mechanism in
physiology. Voluntary hyperventilation as a cause will lead to decreased PCO2.
If increased PCO2 is the cause, then it will stimulate increased ventilation. In
comparing these two situations, the hyperventilation is the cause in the former
and the effect or result in the latter. Similarly, any case of hypoventilation will
cause an elevation in the alveolar/arterial PCO2 (hypercapnia). Hypoventilation
can also be an effect of hypocapnia. Distinguishing the cause/effect (chicken nor
egg?!) in every scenario will help the student to understand homeostasis,
compensatory feedback in Physiology.
8. How does CO2 participate in two ways to ensure adequate oxygen supply to
exercising muscles?
Answer
The local increase in tissue CO2 helps to unload more oxygen from blood. The
local CO2 also vasodilates the blood vessels to increase the perfusion to the
exercising muscles.
Concept
Carbon dioxide is the major metabolic byproduct from the cellular processing of
energy substrates namely carbohydrates, lipids, proteins. Increased active muscle
contraction needs more oxygen and produce more CO2.
The increased supply of oxygen is partly contributed by increased alveolar
ventilation. In moderate exercise, however, relatively constant arterial PCO2
cannot account for the stimulation of a sustained hyperventilation during
exercise.
However, at the tissue level, CO2 has definite actions that increase both the
unloading of oxygen to the cells and the increased blood tissue perfusion. The
local tissue PCO2 is higher than 40 mmHg. Blood that are exposed to this higher
PCO2 will have a decreased hemoglobin affinity for oxygen. Hemoglobin
“loosens up” and release more O2 to the cells. This is called Bohr’s effect which
is also observed when the local tissue pH is less than 7.4.
Physio-lyrics to popular tunes. This composition highlights the beneficial effects of tissue CO2 and lower
pH in unloading of oxygen to the cells. The CO2/pH Bohr’s effect reduces the hemoglobin-O2 affinity, and
from the cell’s perspective, this has a positive effect on the cellular O2 supply
Metabolite vasodilators also include CO2. The arteriolar smooth muscle
relaxes and vasodilates in response to local tissue hypercapnia. The skeletal
muscle blood flow is increased in proportion to the muscle cellular metabolism.
Thus, we have an example of a “physio-synthesis” involving CO2! The
student can train herself to have a mental habit of integrating, associating, and
finding linkages between different situations that involve the same molecule or
same physiologic principle or event like in membrane transportation.
It is also a fascinating “coincidence” that besides CO2, all other metabolites
that have a vascular effect are vasodilators in the respective tissue, e.g., the
adenosine in coronary circulation. The student can look out and discover for
more organizing patterns and mechanistic design in physiology.
9. How will an enlarged functional residual capacity (FRC) affect the alveolar
air CO2?
Answer
The alveolar air partial pressure of CO2 will increase above 40 mmHg.
Concept
FRC is the air in the lungs at the end of a normal resting expiration. The inspired
tidal volume of the next breath will mix with this FRC en route to the alveolar
gas exchange region of the lungs. Carbon dioxide diffuses into the alveoli since
there is a PCO2 partial pressure gradient between pulmonary blood (entering the
alveoli at 46 mmHg) and the alveolar air (controlled at 40 mmHg).
One can picture that the alveolar air PCO2 is an equilibrium value, a balance
between the release of CO2 from blood and the removal of CO2 in the expired
tidal volume. The FRC can be viewed as a buffer air region through which the
expired CO2-rich alveolar air and the inspired CO2-poor air moves.
If the FRC is enlarged, a condition that develops in chronic obstructive lung
disease, the abnormal increased air reservoir buffer will alter the alveolar air
PCO2. The balance of the air inflow and outflow will be changed to a higher
alveolar air PCO2 (simplistically, the student can see this as a larger FRC region
for CO2 to get out from). When this happens, the partial pressure gradient for
optimal diffusion of CO2 from pulmonary blood into alveolar air will be
reduced.
FRC, the end-expiratory lung volume at rest, includes both the anatomical
dead space and the alveolar respiratory space. The residual volume at the end of
a forced expiration still includes the anatomical dead space and a reduced
alveolar respiratory space/zone.
10. Why is the diffusion coefficient for CO2 at the alveolar capillary membrane
higher than for oxygen?
Answer
The much higher solubility of CO2 accounts for greater net diffusion coefficient
for CO2 through blood/air medium.
Concept
CO2 is a bigger molecule than oxygen. In air, the diffusion of oxygen is expected
to be greater than for CO2. However, when diffusion is considered between
alveolar air medium and pulmonary blood, the solubilities for CO2 and oxygen
has to be factored in. Carbon dioxide is more soluble in blood. The amount of a
gas dissolved in solution is described by Henry’s law, which states that the
dissolved gas content is dependent on the gas partial pressure and the solubility
coefficient. For oxygen, it is 0.003 ml O2/dL blood/mmHg, whereas it is much
higher for CO2 at 0.07 ml CO2/dL blood/mmHg. Dissolve CO2 is thus a higher
fraction (5 %) of total blood CO2 content than dissolved O2 (2 %).
The diffusion coefficient for CO2 is about 20 times higher than the diffusion
coefficient for oxygen. For the same partial pressure gradient across the alveolarcapillary membrane, CO2 diffuses 20 times faster than O2. We can see this
diffusive difference in the smaller partial pressure gradient for CO2
(46/40 mmHg) than that needed for O2 (100/40 mmHg).
The diffusion capacity for CO2 across the alveolar-capillary membrane is
governed by Fick’s law of diffusion. In addition to the gas diffusion coefficient,
the area available for diffusion and the thickness of the alveolar-capillary (a-c)
membrane are also influencing factors.
In several occupational-related pulmonary disease, there is thickening of the
a-c membrane. This will interfere with lung oxygenation and equilibration of
oxygen may not be achieved in the short pulmonary capillary blood transit time.
This “alveolar-capillary block” of gas diffusion is not as great a problem with
CO2 diffusion because of its greater diffusion coefficient. Thus, hypoxia and not
hypercapnia is the key pathophysiology in “a-c” diffusion block.
© Springer International Publishing Switzerland 2015
Hwee Ming Cheng, Physiology Question-Based Learning, DOI 10.1007/978-3-319-12790-3_10
10. Respiratory Control
Hwee Ming Cheng1
(1) Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
Hwee Ming Cheng Email: chenghm@ummc.edu.my
We breathe on an average 10–12 times/min. The volume of air we breathe in and
out is also relatively constant, although you are unaware of the air movement
when reading this page. When we are physically more active, both the frequency
and the depth of each breath increase. How does our body maintain adequate
ventilation at rest and step up the respiratory function during exercise?
1. Which is the major chemical that controls normal breathing?
Answer
The main chemical regulator of respiration is carbon dioxide.
Concept
Breathing to stay alive is naturally linked with breathing in oxygen from the air.
The respiratory control mechanisms in the body in reality are more sensitive to
the CO2 in the extracellular fluid (ECF). Regulation of respiration is integrated
by neurons in the brain stem which receives inputs from the peripheral arterial
chemoreceptors. In the brain stem, there are also central chemoreceptors that
sense CO2 changes in the blood. There are a number of observations that account
for the need for greater sensitivity to CO2. The neurons are particularly affected
by changes in pH of the ECF. An increased CO2 produces an acidotic
environment which depresses neuronal activity. For oxygen, even when the
partial pressure is reduced to 60 mmHg from 100 mmHg, the hemoglobin-O2
saturation is still about 90 %. Hypoxia only stimulates the peripheral
chemoreceptors (carotid and aortic bodies), whereas for CO2, both the central
and peripheral receptors respond. Part of the chemoreceptor response to CO2 is
indirect via the generation of protons from carbonic acid. The central
chemoreceptors within the brain stem are sheltered from hydrogen ion formed
outside the blood brain barrier. However, CO2 can diffuse into the brain
interstitial space and be converted to H+. The proton generated with the brain
stem then stimulate the central chemoreceptors. Increased afferent inputs from
both peripheral and central chemosensors to the respiratory control neurons in
the brain stem will then increase both the tidal volume and the frequency of
breathing.
The integrated circuit of respiratory neurons in the brain stem generates the autorhythmic “pacemaker”
activity that governs a respiratory cycle. These respi-neurons can be overrided or bypassed by cortical
signals (e.g., voluntary hyperventilation of breath holding). The arterial peripheral chemoreceptors provide
feedback sensory signals on pH, PO2, and PCO2 in blood. In the brain stem, there is another group of
central chemoreceptors, in proximity to the respiratory neurons
2. What central nervous-system neurons produce increased depth but decrease
frequency breathing in a person during voluntary action?
Answer
Voluntary control of the lung mechanics is via cortical neurons, and the motor
efferents bypass the involuntary respiratory control neurons in the brain stem.
Concept
Breathing is unique in that there are both an automatic as well as a voluntary
control. You are not conscious of your breathing while reading this page;
respiratory pacemaker neurons sets the resting depth and rate of breathing. You
can hold your breath at will (you must go under water in a swimming pool!), or
can hold your breath at will (you must go under water in a swimming pool!), or
you can take a deep breath. When you do some deep, slow breathing exercises,
the inspiratory skeletal muscles (diaphragm, external intercostals muscle)
receive action potentials down their respective alpha motor neurons.
Clinically, a patient can sometime lose the functions of the respiratory brain
stem neurons, either through physical trauma or disease. In such conditions, the
person can still stay alive by a conscious effort in breathing. This is obviously
exhausting. And, when the patient retires to sleep, she is put on a respirator. This
restricted breathing, confined and sustained only by voluntary action, is called
“Ondine’s curse” after a tale, where the jealous Ondine punished her lover by
taking away his normal breath since he became unfaithful and broke his vow to
love Ondine “with his every breath”! Sighing and yawning are basically also
involuntary reflexes, but they can also be voluntarily “imitated”!
3. How does voluntary hyperventilation increase the time a person can remain
under water?
Answer
Hyperventilation produce a hypocapnia that delays the time for the carbon
dioxide to build up in the body to stimulate the respiratory center.
Concept
This is another example of the greater sensitivity of the respiratory response to
CO2 compared to oxygen. The student may associate the voluntary
hyperventilation with more oxygenation of the blood and thus a longer
submerged time under water. The “break-point” at which the person remains
under water can no longer suppress the urge to breath which is actually due to
the strong stimulus of increasing CO2 in the ECF.
Quantitatively, the hyperventilation actually does not increase much the
blood oxygen content. This is, because even at normal resting rate of breathing,
the hemoglobin-oxygen saturation is 97 %, and Hb-bound O2 makes up most of
the oxygen content with a small percentage as dissolved oxygen. Does then the
hyperventilation that accompanies exercise serve any physiologic role if
increased oxygenation is not a primary benefit? In line with the question above,
hyperventilation has an essential role in removing more CO2 that is produced by
more cellular metabolism during physical activity. The alveolar partial pressure
of CO2, PCO2, is determined by the ratio of cellular CO2 production and the
alveolar ventilation as expressed in the alveolar ventilation equation:
During moderate physical activity, the PCO2 in alveolar air and
thus the arterial blood is relatively unchanged. The higher rate of CO2
production is balanced by the increase alveolar ventilation. The interesting
question in exercise is then, “How is the hyperventilation stimulated if not by
any increase in CO2?” (see question 5 below).
The peripheral arterial vascular chemosensors that serve respiratory control are sensitive to three blood
parameters. Decreased partial pressure of O2 (PO2), increased PCO2, and acidic blood pH will activate the
carotid/aortic chemoreceptors to send stimulatory impulses to the respiratory neuronal center in the brain
stem
4. Why does the prolonged, increased voluntary breathing produce dizziness in a
person?
Answer
Cerebral vasoconstriction due to the induced hypocapnia.
Concept
Increased ventilation produces a respiratory alkalosis, since the CO2 is “blown”
off by the lungs. The cerebral arterioles are particularly sensitive to changes in
blood CO2. A reduced partial pressure of CO2 will constrict the cerebral vessels.
This lessens the cerebral blood flow and gives the sensation of giddiness.
This arteriolar response to CO2 is also part of the intrinsic autoregulatory
mechanism of cerebral blood flow. The cerebral vasculature has the inherent
ability to maintain a relatively constant perfusion in spite of blood pressure
fluctuations over a certain autoregulatory range (60–160 mmHg). If there is an
acute decrease in cerebral flow, soon the local CO2 in the brain tissues builds up.
The cerebral arterioles will then vasodilate and blood flow is sustained. This is
an example of a physiologic role of CO2, a gas which should be viewed more
than just a metabolic end product that needs to be eliminated by the lungs during
expiration.
If the decrease in cerebral blood flow is due to hypovolemia/hypotension, it
is useful to contrast the local compensatory cerebral vasodilation with the need
to sustain an adequate head-driving arterial blood pressure. Concurrent with the
reduced cerebral vascular resistance, there will be a systemic increase in the total
peripheral resistance (TPR). The compensatory increase in TPR is effected by
baroreflex activated sympathetic nerve action on selective arteriolar
vasoconstriction (including skin, splanchnic, renal).
5. How do the blood pH and the CO2 change during heavy exercise?
Answer
There will be a decrease in blood CO2 due to stimulation of respiration by lactic
acidosis.
Concept
During voluntary hyperventilation (question 3 above), there can be an increased
in arterial blood PO2 and a respiratory alkalosis due to a decreased in PCO2.
Surprisingly, in moderate exercise like jogging, the arterial blood PO2 and PCO2
remain unchanged. How then is exercise hyperventilation stimulated and
sustained? There are evidences that muscle afferent mechano-as well as muscle
chemoreceptors provide some of the stimulatory inputs into the respiratory
neurons in the brain stem. There could also be, not easily detectable by
conventional measurements, rapid fluctuations in the blood gases that maintain
the hyperventilatory stimulus.
The situation during heavy exercise is different from that in moderate
physical activity. The imbalance between cellular metabolic needs and the
oxygen supply soon result in a lactic acidosis. This metabolic acidosis will now
stimulate the peripheral chemoreceptors to increase alveolar ventilation. The
arterial blood PCO2 will become less than 40 mmHg. The compensated blood
pH by the lower PCO2 will still be acidic as lactic acidosis is the primary cause.
Blood pH is determined and reflected by the ratio between the chemical buffer,
bicarbonate/carbonic acid base/acid component pair. Lacticacidosis will reduce
the bicarbonate and the compensatory ventilation will decrease the carbonic acid
that is formed by the hydration of CO2.
The increased alveolar ventilation during physical activity is primarily for eliminating CO2 from the
ECF/blood rather than to increased blood oxygen content. Accumulation of CO2 will make the ECF/blood
acidic, and neuronal functions are suppressed by acidosis. Increased rate of O2 delivery to cells are effected
by a greater cardiac output rather than by lung oxygenation since a higher ventilation rate does not
markedly increase oxygenation to above normal blood O2 content
6. How do blood pH and CO2 change during ascent to high altitude?
Answer
Hypoxia induced hyperventilation produces a respiratory alkalosis.
Concept
Concept
Exposure to low-inspired oxygen concentration in the atmospheric air will lead
to stimulation of alveolar ventilation. Do not imagine like some students that the
greater physical effort of climbing is the predominant stimulus for the increased
breathing (keep in mind that the ascent is a slow, enjoyable one generally!). The
compensatory hyperventilation produces hypocapnia which alkalines the blood.
The respiratory alkalosis opposes the hypoxic stimulation since CO2 is the more
potent chemical regulator of respiration. Thus, it will take several days for the
person to acclimatize to high altitude. Part of the acclimatization process
involves excretion to increase bicarbonate in the urine. This compensatory renal
event will help to decrease the pH of the brain interstitial fluid that bathes the
central chemoreceptors. Bicarbonate is the main base in the ECF and a
component of the major chemical buffer system, bicarbonate/carbonic acid in
ECF.
Mountain enthusiasts are prescribed a drug that promotes urinary bicarbonate
excretion to hasten acclimatization. This drug is an inhibitor of the enzyme
carbonic anhydrase C@. The C@ action at the nephron is essential for the
normal reabsorption of filtered bicarbonate.
Note in this mountain top scenario, the blood PO2 is lower than 100 mmHg
(decreasing value with increasing altitude). The blood PCO2 is also lower than
40 mmHg due to the compensatory hyperventilation.
Compare the situation in heavy exercise at sea level—the blood PO2 can be
slightly increased, and this is accompanied by a reduced blood PCO2 due to the
lactic acidosis stimulation of breathing.
Local changes in alveolar air PO2 or PCO2 will act to optimize ventilation/perfusion matching. In
underventilated alveoli, the decreased alveolar PO2 will produce hypoxic pulmonary vasoconstriction
(HPV). If the alveolar PO2 is all low, as at high altitude, this HPV can lead to pulmonary hypertension. In
underperfused alveoli, the lower alveolar PCO2 will bronchoconstrict to shunt airflow to better perfused
alveoli. Note and distinguish these PO2 and PCO2 lung effects from the arterial and central chemoreceptor
effects to blood PO2, PCO2 changes
7. How does decreased oxygen supply to the brain produce a reflex
protective cardiovascular response?
Answer
The central ischemic response is due to the direct activation of the
cardiovascular control neurons in the brain stem.
Concept
Hypoxia does not stimulate the central chemoreceptors but only the peripheral
arterial chemoreceptors at the aortic and carotid bodies. Generally, the
respiratory neurons in the brain stem receive major inputs from the
chemoreceptors. The cardiovascular regulatory neurons are also located in the
brain stem. In situations when there is threatened ischemia of the brain, hypoxia
can activate a direct emergency reflex response from the brainstem cardiac and
vasomotor neurons. This is logically linked to, e.g., hypovolemia/hypotension as
a result of blood volume loss. In order to maintain cerebral perfusion, the
hypoxia acting on the brain stem produces a compensatory reflex similar to the
baroreflex that responds to the hypotension. Tachycardia and increased TPR are
part of this central ischemic response that aimed to elevate the arterial blood
pressure to life-sustaining value.
In the case of a reduced cerebral blood flow that is caused by a “head” factor,
i.e., increased intracranial pressure, a similar central ischemic reflex will be
triggered. Interestingly, the increased blood pressure (above normal) will then
result in a baroreflex bradycardia in this case of a mechanical compression of
cerebral vessels by fluid pressure in the closed brain box. This
hypertension/bradycardia paired events resulting from compensatory feedback
mechanisms to the elevated intracranial pressure is also called “Cushing reflex.”
8. Compare the venous blood PO2 in stagnant and histotoxic hypoxia.
Answer
There will be a decreased PO2 instagnant hypoxia and an increased PO2 in
hitotoxic hypoxia.
Concept
Hypoxia should be viewed from the perspective of the cell. The cell is the
consumer target of the function of the cardiorespiratory system in terms of
oxygen delivery. As long as the cells are not able to have enough oxygen for its
metabolic needs, a hypoxic condition is present. In stagnant hypoxia, the
oxygenation is normal at the lungs. However, an inadequate blood flow cannot
supply the cells although the blood oxygen content is normal. This, e.g., occurs
if the heart fails and cannot pump sufficiently to maintain a normal cardiac
output. The rate of oxygen delivery milliliter O2/min is equal to the oxygen
content x of the cardiac output. A longer transit time during stagnant hypoxia at
the tissues will permit the cells to extract more oxygen from the capillary blood.
However, the unloading of O2 to the cells is still limited by the partial pressure
gradient. A fresh inflow of oxygenated arterial blood with PO2 of ~ 100 mmHg
is essential to ensure a PO2 gradient for oxygen diffusion and uptake by the cells.
The venous PO2 will be less than the usual 40 mmHg.
The arterial blood PO2 is unchanged in stagnant hypoxia. This is also the
case in histotoxic hypoxia. The hypoxia is not due to oxygenation or any
problem with peripheral blood perfusion. The cells are prevented from using the
oxygen due to, e.g., metabolic inhibitors. Although there is a partial pressure
gradient between capillary blood and the interstitial fluid, no net oxygen diffuses
since the cells are not using the O2. The blood picture characteristic of histotoxic
hypoxia is an elevation of venous blood PO2 markedly above 40 mmHg. If the
cells are completely deprived of O2, the venous PO2 would theoretically be
unchanged from its arterial PO2 value (of course, the patient would be dead and
you would not be asking the laboratory to measure the venous PO2!).
9. Why is high oxygen therapy for chronic pulmonary conditions not
recommended?
Answer
Sensory adaptation of the chemoreceptors to chronic hypercapnia results in the
need for a hypoxic drive to maintain breathing and keep alive.
need for a hypoxic drive to maintain breathing and keep alive.
Concept
Sensory adaptation occurs in receptor mechanisms although some receptors
adapt rapidly and some slowly. Pain or nociceptors adapt slowly and this
obviously has a protective role to inform us of the presence of any lingering
tissue injury. For touch/pressure cutaneous receptors, they adapt, and we
sometimes find ourselves going into the shower with our spectacles on, our
facial receptors adapted to the visual device.
In a patient with long-standing pulmonary disease, the blood PCO2 is slightly
elevated most of the time due to the subnormal alveolar ventilation. The
chemoreceptors, exposed and stimulated by the chronic hypercapnia will
eventually adapt and become no longer responsive to stimulate and maintain
ventilation. What develops in the patient is a switch to a hypoxic drive. A lower
than normal PO2 in the chronic pulmonary dysfunction is now the only driving
stimulus that ensures an adequate alveolar ventilation. This naturally leads us to
see why a high oxygen inhalation may not be helpful but could be detrimental to
the patient’s breathing. Restoring the blood PO2 also removes the only available
hypoxic drive of ventilation. The reduced ventilation will then be insufficient to
eliminate CO2, which will accumulate in the blood. A progressively severe
respiratory acidosis can result.
10. How does the chemoreceptor produce a release of “neurotransmitter” onto
the afferent nerve that inputs to the respiratory center?
Answer
The peripheral chemoreceptor cells senses hypoxia, in particular, the decrease of
partial pressure of oxygen in the arterial blood that perfuses pass the carotid and
aortic bodies. There is an ionic mechanism that translates the hypoxic sensing to
an action potential in the afferent nerve fiber that ends on the chemoreceptor
cells. In chemoreceptor, cells that are potassium channels are sensitive to
oxygen. Lack of oxygen in the chemoreceptors decreases the ionic conductance
of these potassium channels. The reduced K+ efflux leads to depolarization of
the chemoreceptor cells. Calcium influx via voltage-gated channels and a
chemical transmitter is released and stimulate the afferent fiber that supplies the
chemoreceptors.
This hypoxia induced depolarization effect is also seen in the mechanism of
hypoxic pulmonary vasoconstriction (HPV). The pulmonary smooth muscles are
depolarized by hypoxia and contract. This unique HPV has a role in optimizing
ventilation/perfusion matching throughout the lung.
ventilation/perfusion matching throughout the lung.
This contrasts with the systemic arteries, which have potassium channels that
are closed by adenosine tri-phosphate (ATP). Hypoxia will reduce cytosolic
ATP, and this opens the K+ channels. Increased potassium cation efflux
hyperpolarizes the systemic arteriolar smooth muscles and produces
vasorelaxation. Arteriolar vasodilation is part of the compensatory mechanism at
regional blood flow in the systemic circulation including in autoregulation,
active, and reactive hyperemia.
Part III
Renal Physiology
© Springer International Publishing Switzerland 2015
Hwee Ming Cheng, Physiology Question-Based Learning, DOI 10.1007/978-3-319-12790-3_11
11. Renal Hemodynamics and GFR
Hwee Ming Cheng1
(1) Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
Hwee Ming Cheng Email: chenghm@ummc.edu.my
The resting kidneys receive around 20 % of the normal cardiac output. About
90 % of this renal blood flow (RBF) enters the nephrons (estimated
1 million/kidney) to be filtered at the glomerulus. Filtration is a voluminous
event, 125 ml/min or 180 L daily. In a 70 kg male adult, the total body fluid is
42 L of which extracellular fluid (ECF) volume is a third at 14 L. Thus,
glomerular filtration processed almost 13 times the total ECF and reflects a
major role of the kidneys in the homeostasis of the ECF, the “internal aqueous
environment” that bathes all cells. Filtration is the first step in urine formation.
Urine flow rate is about 2 L/day, highlighting a large amount of water
reabsorption from the glomerular filtrate. The final urine that is excreted is the
net output from the three basic renal handling processes for both water and
solutes—filtration, reabsorption, and secretion.
Changes in RBF produce parallel changes in glomerular filtration rate
(GFR). Thus, renal autoregulation of GFR, an essential first step in urine
formation, is linked to autoregulation of RBF. The autoregulatory mechanisms
of RBF (myogenic and macula densa sensing) are explained hemodynamically
by the same “Flow = Pressure/Resistance” equation, the resistance altered being
the preglomerular afferent arteriole. The glomerulus is a unique capillary in
being sandwiched between two arterioles—the afferent and the efferent.
Downstream from the glomerular capillary network separated by the efferent
arteriole is the peritubular capillary, which participates in tubular reabsorption
and secretion.
The glomerular filtration rate (GFR) is determined by the net filtration pressure (nFP). nFP is the balance of
the three Starling’s forces across the glomerular capillary; opposing hydrostatic pressures in the glomerulus
and Bowman’s capsule and the glomerular oncotic pressure
1. What two determinants are used to calculate the GFR?
Answer
The GFR is determined by the product of the filtration coefficient (K f ) and the
net glomerular filtration pressure (nFP).
Concept
The filtration coefficient is dependent on two factors, the surface area available
for filtration of the plasma water and the water or hydraulic permeability. The
student should note that the GFR is not dependent on solute permeability as we
are dealing with the movement of fluid volume not filtered solute load. The
surface area for filtration can be altered by the degree of contraction of the
glomerular mesangial cells. Vasoactive agents can reduce the K f when the
mesangial cells contract.
The glomerulus is a capillary, and so the Starling’s capillary forces are
operative in explaining glomerular filtration. If the students appreciate capillary
dynamics, when this topic was covered under cardiovascular physiology, the
derivation of the net filtration pressure is a wee (meaning as easy as our urine
flow!) In the glomerular capillary, the two Starling’s forces are the hydrostatic
pressure and the plasma oncotic pressure. In the Bowman’s capsule (equivalent
pressure and the plasma oncotic pressure. In the Bowman’s capsule (equivalent
of the interstital space in other tissues), only the hydrostatic pressure is
considered as little protein leaks out from the glomerulus. Hence, the oncotic
pressure in the Bowman’s space is near to zero mmHg.
There are then three Starlings—forces with the glomerular hydrostatic
pressure being the only force promoting filtration. The net filtration pressure is
the arithmetic sum of the three forces.
A few unique characteristic of the glomerular Starling’s forces deserve
mention. First, the glomerular hydrostatic pressure (Pgc) is distinctly higher than
in other microcirculations. Second, the Pgc only drops slightly along the
glomerulus. This relatively constant high hydrostatic pressure is obviously
essential to produce a large GFR of 125 ml/min(or 180 L per day!). The
presence of a postglomerular high resistance efferent arteriole sustains the Pgc
for filtration.
The glomerular oncotic pressure (#gc), on the other hand, increases along the
capillary. From about 25 mmHg at the afferent arteriolar end of the glomerulus,
the #gc reaches about 40 mmHg “downstream.” This increasing #gc is due to the
high filtration fraction in the glomerulus, a value of 20 %, so the plasma protein
is progressively more concentrated along the glomerulus. The value of the #gc in
the GFR equation is therefore not a single value but a mean value.
There is no capillary reabsorption at the glomerulus, and the net filtration
pressure decreases progressively along the capillary.
Normal resting RBF is around 20 % of cardiac output. Note that the filtration
fraction is a portion of the renal plasma flow, not RBF as red cells are confined
within the glomerulus.
2. What is the expected effect of sympathetic action of the afferent arteriole on
filtration fraction?
Answer
The filtration fraction will be unchanged.
Concept
Filtration fraction is the ratio of the GFR to the renal plasma flow. At rest, this
has a value of about 0.2. This means that a fifth of the total renal plasma flow is
filtered. If the renal sympathetic nerve vasoconstricts only the preglomerular
afferent arteriole (which never happens in vivo, see next question 3), we can
think about the effects on RBF and the GFR.
There will obviously be a decrease in RBF (the renal plasma flow is just
~ 55 % of RBF if the hematocrit is 45 %) with the increased vascular resistance.
The effect on GFR will be mediated by any effects of sympathetic nerve on the
Starling’s forces that contribute to the net filtration pressure that produce the
GFR. Since the glomerulus is “downstream” from the afferent preglomerular
arteriole, the hydrostatic pressure that promotes filtration will be reduced. GFR
will be decreased.
Since sympathetic action decreases both the renal plasma flow and the GFR,
the filtration fraction is unchanged.
This is a good place to talk a little more of the cause and effect mechanisms
in explaining physiology. In the above scenario, the renal sympathetic nerve
activity is the initiating cause acting on the afferent arteriole. The net effect is an
unchanged filtration fraction since both GFR and RBF is decreased in parallel.
If the initiating cause is stated as a change in the filtration fraction (FF), let
us say a increased FF, then the mean glomerular oncotic pressure will be higher.
The student could then reason that an increased mean #gc would lead to a
reduced net filtration pressure and hence a decreased GFR. Thus, if we compare
the two cases, the former has a reduced GFR/unchanged FF (because RBF also
decreases) and the latter, an increased FF/reduced GFR.
If the student is discerning, it will be noted that the former is more
physiologic. This is because an initiating cause given as an increased FF could
already be due to a greater GFR. So, it becomes a case of circular thinking to
work out how this higher FF will effect GFR!
3. What is the expected effect of sympathetic action on Pgc and GFR?
Answer
The renal sympathetic nerve will decrease the GFR and the effect is due to a
reduced RBF and not through any predictable change in glomerular hydrostatic
pressure.
Concept
It ought to be stressed to students that both the renal arterioles are innervated by
renal sympathetic fibers. In other words, sympathetic vasoconstriction or
decreased sympathetic vasodilation will occur concurrently on both the afferent
and efferent arterioles.
The glomerulus is “downstream” from the afferent arteriole and “upstream”
from the efferent arteriole (imagine the renal circulation as a “bloody” river;
bloody used here not as a swear word but as an adjective!). As such, afferent
vasoconstriction will lower the Pgc and the vasoconstricted efferent arteriole will
heighten the Pgc. Thus, it is not easy to predict the overall effects of renal
heighten the Pgc. Thus, it is not easy to predict the overall effects of renal
sympathetic nerve on the Pgc.
However, the renal sympathetic action will always reduce the RBF since
vasoconstriction of either afferent or efferent will decrease renal perfusion.
Whenever RBF changes, there will be a parallel change in the GFR in the same
direction. The student might be surprised to learn that this effect of RBF on GFR
is best explained, not by any predictable effects on Pgc as stated above, but by
the inverse changes in the mean glomerular oncotic pressure #gc when the RBF
changes. Looking back at the GFR formula, the net filtration pressure is (Pgc
minus mean #gc minus Bowman capsular pressure), increased RBF will result in
a decreased mean #gc giving an increased GFR.
The way to comprehend this RBF/#gc phenomenon is to imagine that the rise
in the #gc along the glomerulus takes a comparatively longer time when the
renal perfusion increases.
This also means that the calculated net filtration pressure, assuming it
approaches 0 mmHg will be reached at a point nearer the efferent end of the
glomerulus. We can view this as a larger capillary area where net filtration
occurs. The GFR is higher with a greater RBF because increased RBF causes a
lower mean #gc.
4. What is the role, if any, of sympathetic nerve on renal autoregulation?
Answer
The extrinsic sympathetic innervations to the renal arterioles are not a
contributing input to the Intrinsic renal autoregulation mechanism.
Concept
By the term “intrinsic”, renal autoregulation is able to maintain a constant RBF
over a defined range of blood pressure fluctuations, independent of extrinsic
nerve or circulating hormonal actions.
However, if the conditions in the body require a priority in a dominant renal
sympathetic nerve activity, the neural input will override or “masked” the
underlying RBF autoregulatory mechanisms.
To illustrate, the graphical description of renal autoregulation shows a
controlled flow plateau over the blood pressure changes from 60 to 160 mmHg.
This autoregulation was observed in an in vitro laboratory setup where only the
intrinsic renal mechanisms that maintain flow were documented.
When the blood pressure drops in the body to 80 mmHg, would renal
autoregulation still be effective? In this situation, the dominant renal sympathetic
action is more essential to normalize the arterial blood pressure. The
vasoconstriction of renal arterioles is part of the baroreflex sympathetic
compensatory increase in total peripheral resistance. During hypotension, the
autoregulatory mechanism should vasodilate the afferent arteriole in order to
normalize the RBF. However, the transient reduction in RBF by renal
sympathetic nerve pre-dominates and the intrinsic autoregulation is “masked.”
This physiologic weightage on renal sympathetic nerve is also seen during
exercise. There is some increase in arterial blood pressure during physical
activity. The RBF, however, is not effectively autoregulated to remain
unchanged. There is a need to redistribute the cardiac output to provide more
perfusion to the skeletal muscles during exercise, the blood vessels in the muscle
experiencing vasodilatation.
At the renal vasculature, the increased sympathetic action vasoconstricts the
arterioles. Blood flow to the kidneys is relatively reduced to channel more of the
greater exercise cardiac output to the muscles. This renal vasoconstriction also
serves to maintain the blood pressure during exercise (since the arterioles in the
muscle tissues are dilated, and there is an overall drop in total peripheral
resistance).
5. How does a high protein diet affect, if any, the RBF?
Answer
A high protein diet will lead to an increase in RBF and hence the GFR.
Concept
A high protein diet does not postprandially change the plasma oncotic pressure.
The plasma oncotic pressure is due to the plasma proteins, and this osmotic
pressure is a major force that affects the capillary dynamics at the
microcirculation.
Proteins are digested and the component amino acids are absorbed into the
blood from the intestinal lumen. The plasma amino acids are higher during and
after a meal.
Students who think that a high protein meal increases the plasma oncotic
pressure (#c) will reason that the GFR will decrease since the net filtration
pressure will be lower when the #c (#gc) is higher.
The GFR actually increases within an hour after consuming a high protein
dinner (all you can eat steak buffet!). The hyperamino acidemia is the reason for
the increased GFR. The mechanism interestingly involves the macula densa
tubule-glomerular feedback.
The increased filtered amino acid load leads to a reduction in the NaCl
sensing by the distal tubular macula densa. This is because at the proximal
sensing by the distal tubular macula densa. This is because at the proximal
tubule, the higher filtered amino acids will promote sodium reabsorption via the
sodium-coupled, secondary active reabsorption of amino acids by the proximal
epithelial cells.
The macula densa (McD) detects less of the electrolyte in the distal tubular
fluid and “assumes” that this could be due to a decreased RBF/GFR. The McD
responds by transmitting paracrine signals to the afferent arteriole (less
vasoconstrictor and/or theoretically, more paracrine vasodilators). The McD
activates this effect of the intrinsic renal autoregulatory mechanism and the RBF
increases as the afferent arteriole vasodilates.
6. How is the renal handling of inulin used to derive the value of GFR?
Answer
The GFR is derived from using the unique renal handling of inulin, where
filtered inulin load is equal to the excreted inulin load.
Concept
Almost all known solutes are processed by the kidneys in at least two ways—
filtration and reabsorption (or secretion). Many are filtered, reabsorbed and
secreted, e.g., potassium cations.
The plant molecule inulin is unusual in that all the filtered load of inulin is
excreted and in addition since there is no tubular secretion or reabsorption of
inulin; filtered inulin load = excreted inulin load.
Putting in the components of this relationship,
Looking at this ratio, Uin × V/Pin is the value of an imaginary volume of
plasma that has been “cleared” of inulin per time, and this “cleared” inulin then
appears in the excreted load in urine.
Since inulin is freely filtered, and enters the Bowman’s capsule easily with
the filtered water, the GFR is equal to the volume of plasma water “cleared” of
inulin/time, and this same value of plasma fluid filtered/time enters the
Bowman’s capsule.
Therefore, for any solute that is filtered and reabsorbed back into the
circulating plasma, the renal clearance will be less than the clearance for inulin.
For solutes, in particular, organic solutes/metabolites that are filtered and
secreted before excretion into urine, their renal clearance will be more than
secreted before excretion into urine, their renal clearance will be more than
inulin clearance.
For solutes that are reabsorbed and secreted, the net secretion or net
reabsorption of the solute will determine the value of their renal clearances in
comparison with inulin.
Before the renal clearance was conceptualized and the unique handling of
inulin was found, there was a suggestion that the tubules secrete urine. This is
now seen as incorrect and obsolete. There is no secretion of water by the
nephrons. Remember that the daily GFR is an extremely large volume at 180 L.
On average, we were about 2 L of urine per day depending whether you are in
tropical Malaysia in December or in cold Scandinavia. Thus, there is no
necessity for tubular secretion of water. The renal handling of water is just
Renal handling of solutes by the nephron filter reabsorb and/or secrete the solutes. The excreted amount of
solute, E, is then dependent on either F − R, F + S, or F − R + S
7. How do the peritubular capillary Starling’s forces compare with the forces at
the glomerulus?
Answer
The plasma oncotic pressure is higher than the hydrostatic pressure along the
length of the peritubular capillary.
Concept
In the glomerular capillary, the hydrostatic pressure starts high at ~ 50 mmHg
and is relatively stable along the glomerulus, sustained by the efferent high
resistance smooth muscle structure. The glomerular oncotic pressure, lower than
the glomerulus along the capillary however rises to about 40 mmHg due to the
high filtration fraction.
The peritubular blood is the end glomerular blood that exits from the efferent
arteriole. Thus, the peritubular blood has an elevated oncotic pressure compared
to renal arterial blood that supplies the glomerulus. The high vascular resistance
of the postglomerular efferent arteriole causes a significant drop in the
hydrostatic pressure in the peritubular capillary, to less than 20 mmHg. We have
a capillary network that supplies the renal tubules in which the plasma oncotic
pressure is greater than the hydrostatic pressure along its entire length. This will
generate a net reabsorptive Starling’s force at the peritubular capillary. This
unique capillary dynamic, the student will appreciate is nicely tuned to the
functions of the renal tubules in reabsorption of water, electrolytes, and solutes.
The inquiring students may ask “What about tubular secretion?” For
secretion, the solutes are generally organic compounds or metabolites. These
solutes are transported bound to plasma proteins. The free solute is filtered, and
the tubules also secrete the organic solute. There is an equilibrium between the
free and bound solute, so secretion from the peritubular capillary will still occur.
For active transport, there are organic cation transporters (OCT) and organic
anion transporters (OAT) at the baso-lateral membrane of the proximal tubules.
The passive secretion will depend on the availability of a concentration gradient
between tubular fluid and the peritubular capillary/interstitium; there is no
requirement for membrane transporters if the organic solutes can transverse the
cell membranes down its concentration gradient.
Renal clearance is the excreted load/rate (amount/min) divided by the plasma concentration (amount/vol) of
the solute excreted. This gives a value that represents the “imaginary” volume of plasma that has been
“cleared” of the solute that is found excreted into urine/unit time
8. How do intrarenal prostaglandins affect real blood flow?
Answer
Intrarenal prostaglandins have vasodilatory action, and this effect serves to
modulate and prevent an excessive constriction of renal arterioles.
Concept
The renal sympathetic nerve vasoconstricts both renal arterioles. Circulating
hormones like angiotensin II (AII) is a potent vasoconstrictor and enhances the
effect of sympathetic action to increase the renovascular vascular resistance. AII
is indirectly generated when the renal sympathetic nerve releases renin.
Concurrent with the action on renal arterioles, both the sympathetic activity
and AII also increase the production and secretion of prostaglandin paracrines in
the renal tissues. These prostaglandins relax vascular smooth muscle and
counteract the vasoconstricting action of sympathetic nerve and AII. This
intrarenal feedback provides some protection from potential renal ischemia when
arteriolar constriction is intense.
Clinically, the action of renal prostaglandin vasodilators has implications for
patients who are taking anti-inflammatory drugs, which inhibit prostaglandins.
The kidneys in these persons would have reduced ischemic protection in
situations when the renal arterioles constrict strongly.
9. Why is the renal clearance of creatinine suitable to monitor GFR in hospital
setting?
Answer
The renal clearance of creatinine approaches that of inulin clearance as the small
amount of creatinine secreted and excreted is compensated by some laboratory
false-positive for plasma creatinine.
Concept
The renal clearance for inulin (filtered load = excreted load) is the definitive
method for determining GFR. In the renal wards, it is not convenient to
administer an exogenous solute like inulin to determine for changes in renal
function. The renal clearance of an endogenous solute, creatinine is used
regularly.
The renal tubules handle solutes, and water filtered at the glomerulus. The membrane permeabilities of
specific segments of the tubules are hormonally regulated with regard to transport of certain solutes and
water. Adrenal aldosterone increases both luminal membrane permeabilities to potassium and sodium.
Posterior pituitary vasopressin (ADH) increases the water permeability of collecting ducts during negative
water balance
Creatinine is a metabolite, released into blood at a relatively constant rate.
The excetion of creatinine is by filtration and secretion. Although the calculated
renal clearance will be overestimated because of the excreted load Ucr.V, this is
coincidently compensated by some overestimation of plasma creatinine by
current laboratory analysis. Thus, the renal clearance of creatinine approaches
that of inulin clearance.
In most cases, the physician requests for only one blood sample
determination of plasma creatinine as an indicator of GFR. This is accepted, as
there is an inverse relationship between plasma creatinine and GFR. Plasma
creatinine (Pcr) will be elevated if GFR drops. The graph is not linear and the
sensitivity is poor just below normal GFR value of 125 ml/min. However, the
operating range in most clinical settings falls on the steel portion of the GFR/Pcr
curve and is thus useful to monitor for improvement or deterioration in GFR as
an indicator of renal function.
10. Which factor(s) in the GFR equation is altered by a vasodilator?
Answer
The main change will be a decrease in the mean glomerular oncotic pressure
which results in an increase in the net filtration pressure.
Concept
This scenario reemphasizes the points made in question 3 above. Vasodilation
occurs at the renal arterioles when the renal sympathetic nerve discharge is
reduced. There is no dual innervation by parasympathetic vasodilator nerve to
the renal arterioles (an important exception to the presence of parasympathetic
vasodilator nerve is the fiber that regulates penal erection).
The RBF will increase, and this will increase the GFR. The higher GFR will
also increase the filtered load (GFR × filtrate concentration of solute). There is a
natural tendency to imagine that increased RBF should raise the hydrostatic
pressure in the glomerulus as the primary change in increasing the net filtration
pressure and GFR.
If we consider the separate effects of decreased sympathetic action on the
afferent and efferent arteriole resistance, and how that changes the Pgc, it
becomes clearer that Pgc is not the contributing factor.
Afferent vasodilation should increase the Pgc, while efferent vasodilation
would permit more blood outflow from the glomerulus upstream and lower the
Pgc. Thus, the opposite potential change in the Pgc with reduced
afferent/efferent vascular resistance may leave the Pgc little altered and not
necessarily an increased Pgc to produce a greater GFR.
Since the hydrostatic pressure in the Bowman’s capsule is unaffected by
increased RBF, the only Starling’s force remaining is the (mean) glomerular
oncotic pressure. We would, then, have to conclude that an increase in RBF with
a vasodilator agent will lead to a decrease in the mean oncotic pressure in the
glomerulus.
With a vasoconstrictor, the K f component can also be reduced since the
mesangial modified smooth muscle cells contract and decrease the surface area
for filtration.
© Springer International Publishing Switzerland 2015
Hwee Ming Cheng, Physiology Question-Based Learning, DOI 10.1007/978-3-319-12790-3_12
12. Tubular Function
Hwee Ming Cheng1
(1) Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
Hwee Ming Cheng Email: chenghm@ummc.edu.my
The renal tubules have many similarities to the digestive tract. This may sound
odd. At both epithelial cells in the gastrointestinal tract and in the renal tubules,
the reabsorption and secretion processes are key events. The epithelial cells are
polarized cells and serve the unidirectional reabsorptive and secretory
transmembrane transport events.
The term “Renal handling” refers to the triad renal processes of filtration,
reabsorption, and secretion. What is excreted in urine is the net event of the three
renal epithelial cellular activities. The general sequence is Excreted = Filtered—
Reabsorbed + Secreted. Not all solutes handled by the nephron undergoes all
three processes. Glucose is filtered and reabsorbed—there is no tubular secretion
of glucose. This is the same nephronic scenario for water and sodium. The
secretion of water to produce urine is a nineteenth-century theory!
The filtrate has a long journey from the Bowman’s capsule to the collecting
ducts, en route the loop of Henle (the original U-tube!). Some solutes like amino
acids and glucose is transported entirely by the proximal tubules. More
commonly, different segments of the nephron and collecting ducts modify the
solute concentration in the tubular fluid, either by secretion or reabsorption or
both.
As in the intestines, water reabsorption flows solute absorption. This is
named “iso-osmotic” water reabsorption at the proximal tubule. The glucose in
chyme and glucose in filtrate are transported similarly by secondary active
mechanism using sodium-linked glucose cotransporter energized by the Na/K
ATPase. Both the renal epithelial cells and the gastric parietal cells secrete
hydrogen ions, for blood pH control and gastric digestion, respectively. The
hydrogen ions, for blood pH control and gastric digestion, respectively. The
generation of hydrogen ions in renal tubular and gastric parietal cells require the
catalytic action of carbonic anhydrase.
For organic solutes (other than especially glucose, amino acids obviously),
being products of metabolism of foods or drugs, they are in general filtered and
secreted. There are family groups of luminal/basolateral transporters that are
dedicated to the active secretion of either organic cations or organic anions. The
cationic and anionic polyspecificities of these organic solute transporters make
economic sense when we consider the thousand of organic molecules that need
to be secreted by the renal tubules.
Urea, produce of protein metabolism is a little unusual in being reabsorbed at
the proximal tubule and secreted at the loop of Henle during urea recycling
(reabsorbed from the inner medullary collecting ducts). This urea “merry-goround” is potentiated by the hormone vasopressin and contributes to the
hyperosmotic renal medulla that has an essential role in the urine-concentrating
ability of the kidneys.
The epithelial cells of the renal tubules is a controlled long-processing line
that determines the composition of the excreted urine. The urine chemical and
osmotic profile is a reflection of the sequential cellular work that has gone on
“upstream” along the tubule. The electrolyte balance, water balance, and pH
balance are achieved by the reabsorptive and secretory capacities of the renal
tubules. Trumpet the tubule!
Two intrinsic mechanisms effect renal autoregulation of blood flow and glomerular filtration rate. The
direct preglomerular afferent arteriolar response is called the myogenic mechanism. The macula densa of
the distal tubule is involved in what is known as the tubuloglomerular feedback
1. Why does a decrease renal blood flow lead to uremia?
Answer
There is less filtration of urea and more reabsorption of urea when the renal
blood flow and thus, the glomerular filtration rate (GFR) decreases.
Concept
Renal failure is accompanied by a reduction in GFR. The decrease in GFR can
be due to intrarenal pathophysiology or to prerenal causes. The latter includes a
drop in renal blood perfusion. In renal failure, there is an accumulation of solutes
that are normally excreted in urine. This blood profile is called uremia (“urine in
blood”) and one major solute that is elevated in blood is urea.
Urea is handled by the nephrons via filtration and reabsorption at the
proximal tubules (there is secretion of urea at the renal medulla that contributes
to the hyperosmotic renal interstitium). When the GFR decreases in renal failure,
less urea is filtered to be excreted. In addition, the proximal tubules also
reabsorb more urea from the tubular fluid when the GFR is reduced.
The reason for this is that normally, the passive reabsorption of urea occurs
when the urea becomes concentrated as water is reabsorbed at the early proximal
segment.
When the GFR and thus the tubular fluid flow is reduced, the water
reabsorption still takes place and the urea concentration becomes higher than
usual due to the lower tubular fluid flow. More passive reabsorption of urea
down a greater concentration gradient is promoted. Urea accumulates in the
blood.
There is a proportionate relationship between urine flow rate and urea
excretion. When the urine flow rate is reduced in renal failure due to poor GFR,
urea excretion is decreased. Urea is raised in the blood. Note that when we talk
of urea excretion, it is not urine urea concentration but urea excreted load. In
diuresis, we can expect the urine urea concentration to be less, but the excreted
urea load (concentration × urine flow rate = mg urea/time) is higher.
2. How is the sodium electrochemical gradient utilized for tubular transport?
Answer
The sodium electrochemical gradient provides the potential energy for the
solutes that are co-or countertransported when sodium moves down its gradient.
Concept
Many solutes are transported by the renal tubules using secondary active
transport. This secondary active mechanism utilizes in a majority of cases, a
sodium electrochemical gradient to provide the potential energy for the solute
transport. The sodium gradient is established and maintained by the Na/K
ATPase pump that is active at the basolateral membrane of the tubular cells.
At the luminal membrane side, the filtered sodium concentration is the same
as the plasma concentration at 140 mmol/L. The intracellular sodium
concentration in the proximal cells is low ~ 15 mmol/L and the inside of the
luminal membrane is slightly negatively charged as for all living cells. There is
thus an electrochemical gradient of sodium and this cationic gradient is exploited
by the renal tubular cells to move solutes.
Both glucose and amino acids in the glomerular filtrate are completely
reabsorbed by the proximal tubular cells via sodium symporters. For tubular
hydrogen ion secretion, a sodium-hydrogen exchanger at the luminal membrane
is part of a similar secondary active transport for the proximal epithelial cells.
From the perspective of solute transport, we say that sodium helps or aids the
movement of solutes across the luminal membrane. Viewed from the angle of
sodium handling by the nephron, the movement of solutes linked to sodium
gradient are actually moving or reabsorbing sodium into the tubular cells. Once
inside the cells, the sodium is pumped out at the basolateral membrane by the
Na/K ATPase into the interstitum and enters the peritubular capillary. The
presence of different membrane transporters at the luminal/basolateral sides
enables the functionally polarized renal epithelial tubular cells to transport solute
unidirectionally.
3. How is potassium transported at the proximal tubule?
Answer
Filtered potassium is passively reabsorbed at the proximal tubule via the
paracellular route.
Concept
At the proximal tubule, the reabsorption of potassium is similar to the renal
handling of urea. The reabsorption is passive and requires prior generation of a
potassium concentration gradient. The iso-osmotic water reabsorption at the
early proximal tubule concentrates the tubular fluid potassium. The potassium
then diffuses down its concentration gradient via the paracellular route to the
interstitum to enter the peritubular capillary.
There should be no passive reabsorption of potassium transcellularly. The
student can derive this claim by looking at some basic physiologic facts.
Intracellular potassium is high in all cells, including at the proximal tubules.
Filtered potassium concentration is the same as in plasma since potassium is
freely filtered. Thus, the concentration gradient is uphill and very steep from the
tubular fluid into the cells. It is not possible for potassium to be reabsorbed in to
the proximal tubular cells. Even after being concentrated, the tubular fluid
potassium will still be less than 10 mmol/L.
Can active reabsorption of potassium then take place instead? This is a
possibility, if there exists a transport membrane pump for potassium at the
luminal membrane. Na/K ATPase could be a candidate; however, all the Na/K
ATPases are localized to the basolateral membrane.
4. Does the renal plasma threshold for glucose change in diabetes mellitus?
Answer
The renal plasma threshold for glucose does not change in diabetes mellitus until
renal complications begins to reduce the GFR in chronic diabetes.
Concept
The threshold indicates that a new event will occur when the threshold is
exceeded or when you walk through the threshold of the door, you enter into a
new environment. The renal plasma threshold for glucose is a concentration
threshold or limit. It is defined as the plasma glucose concentration above which,
glucose begins to be excreted in to the urine.
The renal handling of glucose is filtration and tubular reabsorption. Filtered
glucose is completely reabsorbed at the proximal tubule and no glucosuria is
found in normal urine.
The tubular transport of glucose requires the sodium-linked glucose
transporters (SGLT). These membrane transporters are limited and, thus,
saturable if the filtered glucose load becomes high in the tubular fluid. The
filtered glucose “load” is better understood as the rate of glucose filtration, given
by GFR × Pg (plasma glucose concentration).
Sodium is central to nephron function. Reabsorption of many solutes is actively linked to sodium via
secondary active transport, exploiting the sodium electrochemical gradient. The water reabsorption that
follows sodium also concentrates several solutes for their eventual passive reabsorption (chloride, urea,
K+). Sodium is a key cation solute in the hyperosmotic renal medullary interstitium that drives H2O
reabsroption from the collecting ducts
With increasing filtered load that follows increasing hyperglycemia, a point
is reached when the filtered load just matches the completely saturated sodiumglucoase-linked transporter (SGLT, also called transport maximum rate for
glucose, TmG). At this equilibrium, the elevated plasma concentration value is
termed the “renal plasma threshold for glucose” (#Pg). Above #Pg, the filtered
load exceeds the TmG and the unreabsorbed glucose is excreted in the urine.
The problem in diabetes mellitus is simply (a complex endocrine problem
though!) uncontrolled hyperglycemia due to in adequate insulin action either
reduced hormone secretion or poor receptor binding action at target cells. There
is no change in the #Pg which is related to the proximal tubular function, TmG.
The relationship is written as
In a person with long-standing, chronic diabetes mellitus, the glomerular
filtration is affected first before any further renal pathophysiology involving the
tubules. Since the TmG is still normal, this means that a decreased GFR in
chronic diabetes will then be associated with a higher #Pg. Glucosuria will now
occur at a higher plasma glucose concentration. The #Pg in a normal person is
around 180 mg/dl. In chronic diabetes, glucosuria could still be absent even
when the plasma glucose is already more than 200 mg%.
5. What is the role of glomerulo-tubular balance?
Answer
The glomerulo-tubular balance (g-t) compensates for fluctuations in GFR and
the filtered load by increasing or decreasing the proximal tubular reabsorption of
water and sodium.
Concept
Renal autoregulation of GFR is not a perfect intrinsic mechanism. Fluctuation in
GFR still occur. A second line of defence to respond to acute changes in the
GFR and, hence, filtered load is the g-t balance. The proximal tubule is the
effector in this intrinsic renal pathway.
An increase in GFR will be compensated by an increase in proximal tubular
reabsorption of fluid and solute, mainly sodium and vice versa. How does this
glomerulus/proximal cross talk occur?
One explanation considers the peritubular capillary dynamics that change
with fluctuations in GFR. As an example, an increased in GFR alone will
increase the filtration fraction. This will lead to a higher end-glomerular oncotic
pressure which will exit into and as the peritubular blood oncotic pressure. The
higher GFR will decrease the hydrostatic pressure in the peritubular capillary.
These changes in the peritubular Starling’s forces combine then to promote more
reabsorption of fluid and sodium.
The student should note that this intrinsic g-t balance is effective in euvolemic situation. If the extracellular fluid (ECF and, thus, the blood volume
changes, priority will now be given to compensatory mechanisms that operate to
normalize ECF/blood volume. This means that the g-t balance will be masked or
overridden.
To give an example; when there is a contraction of ECF/blood volume, the
appropriate compensations will include a reduced GFR. The lower GFR will
help to conserve fluid. The proximal tubular reabsorption in g-t balance should
also be reduced if the balance mechanisms is effective. However, in ECF
contraction, the observed event at the proximal tubule is an increased
reabsorption. Together the reduced GFR and the increased proximal recovery of
fluid complement each other to preserve blood volume.
Likewise in ECF volume expansion, there will be an increased renal blood
flow (RBF) and GFR and this is integrated with a decreased proximal tubular
reabsorption in order to excrete more water and sodium. The priority laid on
sodium and water balance (which involves extrinsic renal sympathetic nerve and
hormone actions) overrides the intrinsic g-t balance mechanism.
This renal triangle highlights the two parameters that determine if glucosuria will be present. The filtered
load of glucose (amount/time) in a normal person, even during a high carbohydrate meal, will be less than
the maximum rate of tubular reabsorption of glucose (T m Glu). If the hyperglycemia exceeds the renal
plasma threshold for glucose ( # P Glu ), the proximal tubule can no longer recover all the filtered glucose.
Glucose starts to appear in the urine (U Glu > zero)
6. How is glucosuria related to polyuria?
Answer
The unreabsorbed glucose in the tubular fluid will interfere with the iso-osmotic
reabsorption of water at the proximal tubule, and this results in an osmotic
diuresis.
Concept
Glucose filtered from the glomerular plasma is completely reabsorbed by the
proximal tubule. The reabsorption of glucose (and other solutes) coupled to
sodium transport generates a local osmotic gradient that then drives water
movement at the proximal tubule, water reabsorbed both transcellularly and
paracellularly.
Should the filtered load of glucose exceeds the transport maximum at the
proximal tubule, the glucose remains in the tubular fluid and is osmoactive. The
glucose left behind in the tubular fluid will be excreted in the final urine
(glucosuria).
The presence of unreabsorbed glucose will reduce the iso-osmotic
reabsorption of water, which is normally ~ 70 % of the GFR. An osmotic effect
producing what is termed osmotic diuresis results.
This phenomenon is applied in prescription given to induce an osmotic
diuresis. The solute mannitol is freely filtered but is not transported by any
transporter at the luminal membrane of the proximal tubule. Mannitol then
interferes osmoactively with the water reabsorption.
The carbonic anhydrase inhibitor when taken also causes a mild diuresis
through the same osmotic effect. The enzyme inhibitor decreases the
reabsorption of filtered bicarbonate at the proximal tubule which is normally
~ 80 % of the filtered bicarbonate load. The increased bicarbonate anion in the
tubular fluid is then osmoactive and exerts the mild diuretic effect.
7. Does the rate of filtration contribute to the excretion of hydrogen ions?
Answer
The filtered hydrogen ion is an insignificant amount of total acid excreted daily
since the normal plasma hydrogen ion concentration is around 40 nanoMole/L
(10−9 Mole).
Concept
The daily acid excreted is in the region of millimoles, about 70 mmoles. This
represents the noncarbonic or nonvolatile fixed acid that has to be excreted by
the kidneys. Renal failure is associated with a metabolic acidosis.
The free hydrogen ion in urine determines the pH of the urine. The minimum
urine pH can decrease to at least 4.4. On the pH log scale, this represents a
thousandfold higher concentration for H+ in tubular fluid/urine compared to in
plasma at pH 7.4. Most of the daily urinary acid load in mmoles is excreted as
complexed urinary phosphate and ammonium ions.
The tubular secretion of hydrogen is obviously an active process against a
limiting uphill concentration gradient of a thousand fold. Since even at pH 4.4,
the free H+ in urine is still of the micromole range. This highlights the
importance of urinary phosphate and ammonium to enable the kidneys to excrete
the daily millimolar amount of acids.
The renal epithelial cells of the tubule secrete H+ to fulfill two cellular
missions in acid base balance. The first is the use of secreted hydrogen to “fish”
and reabsorb filtered bicarbonate. Around 80 % of filtered HCO3 anion is
reabsorbed indirectly at the proximal tubule using this hydrogen “fishing” line
dipped into the tubular fluid. The renal tubules also secrete hydrogen ion,
generated from the hydration of CO2 to carbonic acid. Newly synthesized
bicarbonate ions from the dissociation of carbonic acid inside tubular cells are
absorbed into the peritubular capillary.
The two membrane secretors of hydrogen ions are the sodium/H+ antiporter
at the proximal tubule luminal membrane and the H+ ATPase at the intercalated
cells of the collecting ducts.
8. How is the passive secretion of organic acids dependent on pH?
Answer
For passive secretion of organic acids, a higher pH of the tubular fluid favours
secretion and eventual excretion of the acid due to “diffusion trapping.”
Concept
Many organic solutes are either weak organic acids or bases. The proximal
tubules actively secrete organic acids and bases. The organic solutes can also be
passively secreted, if the downhill concentration gradient is available between
the peritubular capillary and the tubular fluid.
To illustrate using organic acids, the unbound free acid (plasma protein binds
to transport the lipophobic organic solute) is filtered. In the tubular fluid, there is
some dissociation of the weak acid and the degree of hydrogen ion and organic
anion separating is influenced by the pH of the tubular fluid.
If the tubular fluid becomes alkaline, more dissociation of the organic acid
occurs. The charged organic anion species will increase. The organic anion will
not be able to diffuse across the lipid rich luminal membrane and is “trapped” in
the tubular fluid.
More dissociation will also mean that the concentration of the undissociated
organic acid will be reduced in the tubular fluid. This will favour the provision
of a concentration gradient for passive diffusion of the organic acid from
peritubular fluid into the lumen of the renal tubules.
The overall process, where diffusion of the organic acid is enhanced and
dissociation of the organic acid “traps” it in the lumen to be eventually excreted
is called “diffusion trapping.”
This tubular fluid pH dependence of passive organic acid secretion is utilized
in the treatment of a person who has swallowed an excess of aspirin. Aspirin is
salicylic acid. The basic bicarbonate is given to the overdosed patient to
alkalinize the tubular fluid. This will promote passive secretion and more rapid
elimination of elevated blood aspirin.
It should be noted that protein-bound organic solutes do not prevent them
from being secreted by the tubules. This is because the protein-bound organic
solute is in equilibrium with the free organic solute. As some of the organic
solute diffuses, this is replaced by the release of some organic solute from the
plasma protein carrier.
9. How does the renal clearance of urea compare to that of inulin?
Answer
Answer
The renal clearance of urea is less than inulin clearance since there is net
reabsorption of urea along the nephron.
Concept
The clearance of inulin is used to determine GFR based on the fact that filtered
inulin rate (“load”) is equal to the excreted inulin load. The solute inulin is freely
filtered and enters the Bowman capsule together in the filtrate.
The unit for renal clearance is volume/min and not the amount of solute/min.
Clearance is a concept that imagines a certain volume of plasma “cleared” of a
particular solute. Of course, in reality, there will be no portion of the circulating
plasma that will be devoid of that solute.
For solutes that are reabsorbed after filtration, some of solute is returned to
the plasma. In this case, the clearance of the solute into urine will be less than
that for inulin, which is neither reabsorbed nor secreted.
For solutes that are both reabsorbed and secreted in different segments of the
nephron, the renal clearance will depend on the net tubular process. For urea,
~ 50 % is reabsorbed at the proximal tubule. There is some secretion of urea at
the loop of Henle of juxtamedullary nephrons during urea recycling, but this is
the urea that is reabsorbed from the inner medullary collecting ducts.
Therefore for urea, there is still net tubular reabsorption. The renal clearance
of urea will be less than the inulin clearance. More urea is excreted (mg/min)
when the urine flow rate is higher. Urea clearance is higher with increasing urine
volume excretion. If the clearance of urea is reduced, e.g., when GFR is low in
renal dysfunction, the decreased urea clearance will result in increased plasma
urea concentration seen in “uremia” of kidney failure.
10. How is the differential tubular reabsorption of sodium along the nephron
linked to renal control of water balance?
Answer
The proximal tubule reabsorbs water iso-osmotically following diverse sodiumsolute transport. The reabsorption of sodium at the ascending loop of Henle
contributes to the generation of hyperosmotic interstitium, essential for water
reabsorption during negative water balance.
Concept
The tubular handling of filtered sodium is linked to both water and sodium
balance control. The major fraction of GFR, ~ 70 %, is reabsorbed at the
proximal tubule. This water reabsorption follows sodium-solute transport when a
local osmotic gradient is generated. The iso-osmotic water reabsorption is
termed obligatory and is not under direct hormonal or neural control (renal
sympathetic nerve and angiotensin II does increase sodium reabsorption here).
The desending loop of Henle is basically impermeable to sodium and no
sodium is reabsorbed. This results in progressive concentration of sodium in the
tubular fluid in the juxtamedullary (jm) nephrons as water is reabsorbed, driven
by the hyperosmotic renal medulla.
At the thick ascending loop of Henle, the sodium is actively reabsorbed and
this active efflux of sodium helps to generate the stratified, hyperosmotic
medullary interstitium. This segment of the jm nephrons is unusual in that it
remains impermeable to water.
The hyperosmotic renal medulla is a prepared condition needed for
reabsorption of water from the collecting ducts, downstream from the Henle’s
loop. During negative water balance, the hormone vasopressin (antidiuretic
hormone, ADH) increases in plasma and the collecting ducts becomes permeable
to water with the insertion of aquaporins at the luminal membrane of the ducts.
Water then moves osmoactively since there is a ready hyperosmotic environment
surrounding the medullary collecting ducts.
When sodium is reabsorbed at the principal cells of the collecting ducts
under the stimulatory action of aldosterone, does water follow the sodium
transport? The student can reason out that this “water follow sodium”
phenomenon should take place, if there is simultaneous action of ADH. The
ADH secretion is increased in negative water balance and the plasma
aldosterone levels are higher in negative sodium balance. Are there situations,
when there are both negative sodium and negative water balance? There are
many common examples—post sweating, post blood donation. In fact any
reduction in ECF volume would result in a negative sodium balance (all fluids
contain sodium) and obviously reduced ECF water volume (an isotonic
contraction, also a negative water balance is detected by volume/pressure
receptors which then stimulate ADH via the hypovolemia). So, in these
situations, we can say that water will follow sodium reabsorption at the
collecting ducts, although this is not a necessary criterion at the jm nephrons,
since the medullary interstitium is hyperosmotic and drives the water movement.
Perhaps in the cortical nephrons where the interstitium is iso-osmotic to
plasma at 300 mOsm/L, this “water follow sodium” event becomes significant,
when the cortical nephrons conserve water.
A different scenario is a person who has a low sodium diet. This hyposodium
intake will lead to a reduced ECF volume since total body sodium determines
ECF volume. There is negative sodium balance and negative water balance,
since the ECF water is reduced.
since the ECF water is reduced.
My student, Annabela Diong creatively drew this when I imagined a Physio female character called
Phyrettie! There are six possible categories of extracellular fluid (ECF) changes based on volume and
osmolarity alterations. During physical activity, sweating will hypertonically contract the ECF. In normal
persons, only hypotonic contraction among the six ECF disturbances cannot be caused…. Why do you think
that is the case??!!
© Springer International Publishing Switzerland 2015
Hwee Ming Cheng, Physiology Question-Based Learning, DOI 10.1007/978-3-319-12790-3_13
13. Potassium and Calcium Balance
Hwee Ming Cheng1
(1) Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
Hwee Ming Cheng Email: chenghm@ummc.edu.my
The two cations are present at relatively low concentrations in the extracellular
fluid (ECF). Potassium concentration in blood is 4–5 mmol/L, and calcium is
lower at around 2.5 mmol/L. The importance of maintaining these physiologic
low concentrations of potassium and calcium imply that the homeostatic
feedback control mechanisms for both cations must be sensitive and rapidly
responding.
The physiologic control of potassium and calcium share the same design in
having regulatory hormones that are not under the hypothalamo-pituitary axis
(hpa) control. The secretion of steroid adrenal hormone aldosterone for
potassium and parathyroid hormone (PTH)/vitamin D for calcium is not
dependent on descending signals along the hpa axis.
The sensors for potassium and calcium reside on the cell membrane of their
respective regulatory endocrine cells. K+ sensors are on the zona glomerulosa
cells in the adrenal cortex and Ca++ sensors on the parathyroid secreting cells.
Both ECF potassium and calcium affect nerve and muscle functions. The
transmembrane potassium gradient determines the resting membrane potential of
excitable cells. For calcium, changes in ECF calcium will alter the excitability of
the nerve and muscle, probably via some steric action at the voltage-gated
sodium channels.
The renal effector control of the electrolyte balance of potassium and
calcium is via actions of the associated hormones acting on the tubular transport
processes of these cations in the kidneys.
At least 70 % of the filtered potassium load is passively reabsorbed at the proximal tubule. Prior isoosmotic
reabsorption of water at the early segment of the proximal tubule concentrates the tubular fluid K+. A
chemical concentration gradient for K+ diffusion via the intercellular junction is generated. The absence of
active K+ “pump” at the luminal membrane does not permit active transepithelial reabsorption of potassium
1. How is the filtered load for potassium and for calcium calculated?
Answer
The filtered load of a solute is the product of the glomerular filtration rate (GFR)
and the filterable portion of the solute; for potassium, this is the plasma
concentration, and for calcium, it would be the free unbound calcium in plasma.
Concept
The filtered load is actually the filtration rate of a solute. For potassium cation,
the filtered load is the GFR multiplied by the plasma concentration (4–
5 mmol/L) since potassium is freely filtered.
Calcium cations are 40 % bound by plasma proteins. The protein-bound
calcium remains unfiltered in the glomerular capillary. The filtered load of
calcium is the GFR multiplied by 0.6 (plasma calcium concentration,
~ 2.5 mmol/L). Of the 60 % filterable calcium in plasma, one fifth of the cation
is also associated as complexes with anions including phosphate, sulphate and
citrate. The calcium ionic complexes are also filtered. The free ionized plasma
calcium is the biological active ionic species.
The student should note that after filtration, both the potassium and the
calcium plasma concentrations at the end of the glomerulus have not changed.
The maintenance of an optimal tubular fluid load from the Bowman’s capsule to the rest of the long stretch
of the nephron is provided by two intrinsic renal mechanisms. The first line of control is renal
autoregulation which includes the myogenic and the tubulo-glomerulal feedback/macula densa responses.
Since renal autoregulation of renal blood flow (RBF)/GFR is not perfect or foolproof, a second line of
regulation is the Glomerulo-tubular balance. This adjusts the degree of proximal tubular reabsorption of
water and sodium in parallel with fluctuations in the filtered water and solute load
2. How does pH of blood affect filtered calcium and potassium concentration?
Answer
Decreased blood pH tends to increase plasma potassium as well as free plasma
calcium and both cations will be filtered more at the glomerulus.
Concept
The plasma potassium level is influenced by acid–base balance. Some acidosis
tends to increase plasma hydrogen concentration. This operates as a result of
intracellularly buffering in all cells that is then accompanied by a transmembrane
K+/H+ exchange phenomenon in order to preserve body fluid electroneutrality in
the ECF/intra cellular fluid (ICF) compartments.
For calcium, plasma albumin contains negatively charged sites that can bind
either calcium or hydrogen ions. Acidotic plasma tends to compete and release
more of the protein-bound calcium and a hypercalcemia can occur. Conversely,
in alkalemia, the free, ionized calcium is decreased by more protein binding,
leading to symptoms of hypocalcemia.
A high-protein diet leads to hyperamino acidemia. The greater filtered amino acid load will enhance sodium
reabsorption via the secondary active Na-linked mechanism. The macula densa downstream at the distal
tubule senses the reduced tubular fluid sodium/chloride. The paracrine effect from the McD on the afferent
arteriole (both part of the juxtaglomerular apparatus) is to produce vasodilation and increased renal blood
flow and glomerular filtration rate (GFR). This protein-GFR effect may be the rationale for a low-protein
diet in patients with reduced renal function
3. Are the respective cation sensors for potassium and calcium homeostasis
located in the kidneys?
Answer
The potassium and calcium sensors are localized on the endocrine cells that
secrete aldosterone and the PTH, respectively.
Concept
Since the normal concentration of both cations are low in plasma, the control
mechanisms that sense and monitor the cationic concentrations have to be
rapidly responding. The natural site for receptors that detect changes in the
calcium and potassium ECF concentrations would be the membrane of the
respective endocrine cells.
For calcium parathyroid glands secrete the PTH in response to hypocalcemia.
The PTH secreting cells have membrane sensors that serve this function. We
would correctly infer that calcium membrane sensors are also found on
endocrine cells that secrete calcitonin. Calcitonin reduces hypercalcemia and the
calcium receptors respond to increased ECF calcium. If ECF calcium has a
direct effect on synthesis of active vitamin D in renal cells, then these cells
should be equipped with calcium receptor mechanisms that would be activated
during hypocalcemia to increase vitamin D production. The triad of hormones,
PTH, vitamin D, and calcitonin, all have actions on the nephrons of the kidneys
to regulate calcium balance.
Potassium sensors that provide feedback in potassium balance/homeostasis
are not located in the kidneys. The kidneys are the site for potassium
reabsorption and hormonally regulated secretion. The K+ sensors are membrane
structures on cells in the zona glomerulosa of the adrenal cortex that secrete
aldosterone. Aldosterone is a steroid hormone and secreted on demand, i.e.,
aldosterone is not made and packaged in vesicles that are released upon
stimulation. There must be a signalling pathway from sensing hyperkalemia by
these adrenal cortical cells to the release of aldosterone into the circulation.
4. How does the reabsorption of potassium at the loop of Henle affect
calcium transport?
Answer
The transepithelial potential generated subsequent to the activity of the Na/2Cl/K
at the ascending loop of Henle favors calcium cation reabsorption.
Concept
The triple cotransporter at the ascending loop of Henle (LoH) is by nature a
neutral cotransporter, moving two cations and two anions simultaneously.
However, some potassium diffuses back into the lumen. The result of the
movement of potassium back across the luminal membrane leads to the
Na/K/2Cl being an electrogenic transporter.
A lumen positive potential difference is created that helps to drive the transport
of divalent cations like calcium and magnesium.
About 20–25 % of filtered calcium is reabsorbed at the ascending LoH via
the paracellular route, driven by the electrical potential.
Since this triple transporter also reabsorbs sodium, the calcium reabsorption
and the sodium reabsorption is coupled here. Clinically, this sodium/calcium
linkage has important implications as loop diuretics acts on the triple symporter
to inhibit sodium reabsorption. Thus, the loop diuretic also has secondary
hypercalciuric effects. This action on increasing calcium excretion is used when
prescribing loop diuretics for hypercalcemia.
5. How does renal failure affect plasma calcium?
Answer
Renal failure causes hypocalcemia that then triggers a secondary
hyperparathyroidism.
Concept
There are a few reasons that explain the reduced plasma calcium in renal failure.
There are a few reasons that explain the reduced plasma calcium in renal failure.
The more obvious reason is that the source of active vitamin D is the kidneys.
Under the action of the PTH, which has hypercalcemic effects, hydroxylation
reactions that produce bioactive vitamin D is stimulated in the renal endocrine
cells. If renal dysfunction affects these cells, plasma vitamin D may be
insufficient to ensure adequate intestinal absorption of calcium.
Renal failure is commonly associated with a decreased excretion of urinary
phosphate. Plasma phosphate accumulates. The hyperphosphatemia then leads to
more complex formation with free ionized calcium. The latter is the bioactive
free calcium. This decreases in plasma calcium, consequent from the increase in
plasma phosphate, triggers secretion of the PTH.
The secondary hyper-PTH can be minimized by giving the patient
“phosphate-binders.” In normals, the PTH has a definite physiologic action in
increasing phosphate excretion in urine by inhibiting phosphate reabsorption at
the proximal tubule. The PTH increases distal tubular calcium reabsorption.
These opposite renal actions of the PTH, combined with the increased bone
resorption, stimulated by the PTH (that releases both calcium and phosphate into
the blood) give a net increase in free ionized calcium that is produced by PTH
action.
The phosphaturic action of the PTH should be remembered and it might help
to think of the PTH as “PhosphaTuric Hormone”!
How might renal failure affect potassium balance. Normally more than 70 %
of filtered potassium is reabsorbed at the proximal tubule. The fine-tuning of
aldosterone regulation of potassium secretion takes place at the collecting ducts.
Thus, the extent and site of renal damage will determine the overall effect on
plasma potassium. An inadequate proximal reabsorption can potentially lose
more potassium in the urine. On the other hand (on the other nephronic site!), a
reduced ductal ability to secrete potassium in response to increased potassium
dietary load can be hyperkalemic.
6. Does diuresis passively or actively affect potassium excretion?
Answer
Increased tubular fluid flow enhances the gradient for passive diffusion of
potassium from the principal cells into the lumen of the collecting ducts.
Concept
Tubular transepithelial secretion of potassium is an active process. There are two
steps in this active secretion. The basolateral membrane adenosin triphosphatase
(ATPase) pumps potassium into the principal cells. Then, intracellular potassium
diffuses passively at the luminal membrane down its concentration gradient in to
diffuses passively at the luminal membrane down its concentration gradient in to
the tubular fluid. The overall tubular secretion is active since the ATPase step is
active.
The increased water excretion is accompanied by a greater secretion of
potassium. This is effected at the luminal passive diffusive second step. Higher
tubular fluid flow will tend to lower the tubular potassium concentration at
luminal side of the principal cell. A steeper concentration gradient promotes
more potassium secretion and hyperkaliuria results.
This hyperkaliuria occurs with action of loop diuretics. Interference of
sodium reabsorption at the loop of Henle causes an osmotic effect due to the
increased tubular fluid sodium. Downstream at the collecting ducts, the osmotic
diuresis secondarily causes more potassium loss into urine by secretion (besides
the concentration gradient effect by greater tubular fluid flow, the greater sodium
load also enhances sodium/potassium “exchange” movements in the principal
epithelial cell and potassium secretion is increased).
A question that might be asked is about the action or rather “inaction” of
antidiuretic hormone (ADH) during normal physiologic response to positive
water balance. Does the water diuresis in the absence of ADH also result in
some kaliuric effects? That would not be a physiologic side complications in
electrolyte control. ADH has been shown to have a stimulatory action on tubular
potassium secretion. Thus, the suppression of ADH reduces somewhat
potassium secretion and this counteracts the kaliuric effect of diuresis.
7. Would you expect the renal compensation for negative sodium balance to
result in a secondary hypokalemia?
Answer
Potentially, the increased aldosterone action to compensate by stimulating renal
sodium reabsorption could also increase potassium secretion, but this will not
make sense or be physiologic.
Concept
Both the homeostasis of ECF sodium and potassium require the key regulatory
hormone aldostereone. The target cell for aldosterone action in sodium and
potassium control is also the same principal cell of the collecting ducts.
Aldosterone acts by increasing the activity of the common membrane pump
shared by sodium and potassium, Na/K ATPase at the basolateral side of the
principal epithelial cell. At the luminal membrane, aldosterone acts to increase
the membrane permeability to sodium and potassium by the addition of more
sodium and potassium ion channels respectively.
sodium and potassium ion channels respectively.
Thus potentially, a compensation and normalization in response to a disturbance
in one cation could lead to a secondary imbalance in the other cation.
However, in negative sodium balance, the ECF and hence blood volume is
reduced. This means the renal blood flow would be decreased and the GFR is
then less than normal. The decreased tubular fluid flow, “downstream” at the
collecting ducts, as a result of the reduced starting GFR would affect potassium
secretion. Lower tubular fluid flow will tend to slow potassium entry across the
luminal membrane into the lumen.
The kidneys are partners with the heart in maintaining ECF/blood volume. The blood volume is a major
determinant of blood pressure, and this fact accounts for the pivotal role of the kidneys in what is termed
the “long-term” control of blood pressure. The kidneys’ volume regulation is tied to the cardiac output
determinant of blood pressure
This fluid effect to decrease diffusion of potassium provides the
counterbalance to any secondary effect of aldosterone (induced by the negative
sodium balance) to stimulate potassium secretion. The potassium balance is
unaltered, which vindicates the physiologic design of the human body.
8. Compare how renal compensate for plasma potassium changes in diarrhea
and in vomiting?
Answer
Potassium is lost in both vomitus and fecal water. The aldosterone secretion
would be inhibited to reduce renal excretion of potassium.
Concept
Hypokalemia is a problem with vomiting and diarrhea. In addition, the volume
contraction will tend to sustain the hypokalemia due to the ECF/blood volume
contraction. Decreased vascular volume will trigger the activation of the sodium
conserving renin-angiotensin-aldosterone system. Aldosterone stimulates ductal
potassium secretion. There is thus the balance between the direct effects of
potassium secretion. There is thus the balance between the direct effects of
hypokalemia in suppressing adrenal aldosterone secretion and the indirect effects
of hypovolemia-induced aldosterone release.
In the metabolic alkalosis resulting from vomiting, the alkalosis will lead to the
transmembrane hydrogen/potassium exchange activity as part of the general
cellular buffering mechanism. This H/K interchange during alkalosis shifts
potassium into cells and aggravates the hypokalemia.
There are other potential inputs that affect ECF potassium during
hypovolemia. Volume/pressure sensing will trigger the effector sympathetic
nerve activity. The adrenal catecholamines are secreted by the sole controlling
neural action of sympathetic cholinergic nerve. Circulating adrenaline has
negative or positive actions on the cellular uptake of potassium which depends
on whether the alpha or beta adrenergic receptors are bound respectively by the
hormone.
9. How is energy used, directly or indirectly to power potassium transport
along the nephron, at the proximal tubule, loop of Henle and the collecting
ducts?
Answer
The sodium/potassium ATPase is the unifying energy nucleus that sets up
conditions for potassium reabsorption and secretion along the nephron. Starting
at the collecting ducts and going upstream, we first see the basolateral membrane
ATPase pumping potassium into the principal cells of the ducts. Potassium then
diffuses into the tubular fluid down its concentration gradient. Here, the ATPase
maintains the high intracellular potassium concentration for the downhill
diffusion of potassium into the lumen.
Midstream at the ascending loop of Henle, we can consider the reabsorption of
potassium as a sodium-linked secondary active transport. The ever-faithful
ATPase maintains a low intracellular sodium concentration in the “loopy” cells.
There is then a sodium electrochemical gradient across the epithelial cells. The
potential energy in this sodium gradient is then exploited at the luminal
membrane by the triple Na/2Cl/K cotransporter. Potassium is brought into the
cells and will presumably diffuse out at the basolateral membrane. Some
potassium will also leak back into the lumen and this generates the lumen
positive potential that is utilized for reabsorption of the cations, calcium and
magnesium paracellularly.
At the proximal tubule, the energy expended by the Na/K ATPase reabsorbs
~ 70 % of the filtered sodium, mainly via solute-coupled sodium mechanisms.
Many of these are sodium symporters, but the sodium-hydrogen antiporter
should not be forgotten as this proximal membrane transporter is the major renal
tubular secretor of hydrogen ions.
Water is then reabsorbed isoosmotically following the sodium/solute
reabsorption. Upon water reabsorption, the potassium is concentrated in the
tubular fluid and at the late proximal segment a concentration gradient for
potassium is present between tubular fluid potassium and interstitial fluid
potassium. Potassium is reabsorbed passively via the paracellular route (tight
junctions are not tight enough to prevent K+ passage!). At least 70 % of filtered
potassium is recovered into the circulation at the proximal tubule in like fashion.
This is an indirect, multistep mechanism from the ATPase-driven active
sodium transport to water movement to generation of K+ gradient for passive
reabsorption.
10. How does the renal handling of potassium change in a low potassium
diet?
Answer
On a low potassium diet, the collecting ducts can begin to reabsorb potassium
instead of secreting the cation when on a normal diet.
Concept
Potassium concentration in the ECF is kept at a low level of less than 5 mmol/L.
Each day, on a normal diet, excess potassium is added to the ECF. The
homeostasis of potassium balance by the kidneys include hormonally fine-tuning
the degree of potassium secretion at the principal cells of the collecting ducts.
The adrenal corticosteroid hormone, aldosterone fulfills this function.
The intercalated cells of the collecting ducts can reabsorb potassium. This takes
place if there is the need to maintain plasma potassium during an episode of low
potassium dietary intake. The luminal membrane of the intercalated cells have
the transporter, potassium/hydrogen ATPase exchanger. This is similar to the
H/K ATPase that secretes acid at the gastric parietal cells.
Potassium is actively pumped into the cells from the tubular fluid against its
concentration gradient. From inside the intercalated cells, potassium then
diffuses out at the basolateral membrane into the interstitium and then into the
peritubular capillary.
Aldosterone has also a positive action in the secretion of hydrogen ions by
stimulating an H+ ATPase also present on the luminal surface of the intercalated
cells. The other hydrogen membrane pump, H/K ATPase is not affected by
aldosterone as this would mean that aldosterone also increases potassium
reabsorption (which will oppose its stimulation of potassium secretion at the
principal cells).
Hypokalemia stimulates tubular ammonia synthesis and increases the ability
of the nephron to excrete hydrogen ions as ammonium NH4 +. In hypokalemia,
potassium exits the renal cells, and there is a mutual replacement of the cation
with hydrogen ion. The resulting decrease in intracellular pH stimulates NH3
synthesis from glutamine.
© Springer International Publishing Switzerland 2015
Hwee Ming Cheng, Physiology Question-Based Learning, DOI 10.1007/978-3-319-12790-3_14
14. Water Balance
Hwee Ming Cheng1
(1) Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
Hwee Ming Cheng Email: chenghm@ummc.edu.my
Our kidneys excrete urine of varying volume—dilute and concentrated urines.
The excreted solutes must be dissolved in water (we obviously cannot urinate
solids!). The range of the volume and osmotic concentration of urine reflects the
ability of the kidneys to regulate and maintain a constant extracellular fluid
(ECF) osmolarity. Changes in ECF are rectified by the kidneys and translated to
changes in urine volume/osmolarity. Osmoregulation is the same as regulating
water balance. Since ECF sodium concentration is the main determinant of ECF
osmolarity, we have three controlled parameters that refer to the same
physiologic homeostasis. These are water balance, osmoregulation, and sodium
concentration (like a three-in-two coffee pack!). We can quite correctly consider
the hypothalamic osmoreceptors as receptors that monitor ECF sodium
concentration.
Osmoregulation, control of water balance, or regulation of ECF sodium concentration all refer to the same
physiological function
If we are overhydrated, we use the term positive water balance. A positive
water balance will at the same time lower the ECF sodium concentration
(hyponatremia) and osmolarity (hypoosmotic). The student should note that
drinking a large volume of water decreases the sodium concentration, but the
total body sodium (sodium balance) is unchanged [see next set of questions on
sodium balance; receptors that monitor sodium balance are a family of
volume/pressure receptors].
The kidneys are unusual in having a medulla that is hyperosmotic. This is
generated by a subpopulation of nephrons (juxtamedullary nephrons) and their
associated peritubular vasa recta capillaries. The hyperosmotic medullary
interstiium is essential for the kidneys to respond to negative water balance by
reabsorbing more water, in concert with the action of the hormone vasopressin
(antidiuretic hormone).
1. How are water balance and osmoregulation related?
Answer
A positive water balance will lower ECF osmolarity and lead to excretion of a
high volume, hypotonic urine.
Concept
Most students are familiar with the book Thesaurus which list synonyms, words
with related meaning. This provides the person a spectrum of words to describe
the same phenomenon in different ways or from different perspectives.
In physiology, the language and terminology commonly used also often
include different names that describe the same physiological control events.
Regulation of water balance and osmoregulation is one example.
Osmolarity of the ECF is determined predominantly by ECF sodium
concentration. A change in the water balance is frequently the cause of either
hypernatremia or hyponatremia. This association is important to note as most
cases of clinical hyponatremia are not due to loss of sodium but retention of
water (in Addison’s disease, there is a loss of sodium).
A positive water balance occurs when a student in a physiology practical
drinks a large volume of water. Potentially, this excess water will lead to
hyponatremia and a hypoosmotic ECF.
The osmoreceptor sensing is rapid and within 30 min, the kidneys will
excrete the excess water to increase and normalize the osmolarity. The water
diuresis is effected as the antidiuretic hormone (ADH) secretion from the
posterior pituitary is inhibited. The hyponatremia will quite soon return to eunatremia.
The three physiological synonyms discussed here are osmoregulation,
control of (ECF) water balance and control of ECF sodium concentration.
2. Why is there no need for water secretion from the renal tubules?
Answer
The renal handling of water is simply filtration minus reabsorption since the
glomerular filtration rate (GFR) is normally 99 % larger than the urine flow rate.
Concept
The tubular secretion of water to produce urine is an obsolete nineteenth-century
theory. With the use of inulin and the concept of renal clearance, normal GFR
was found to be an immense large volume of plasma water filtered daily
(180 L/day). In a 70 kg male adult with a plasma volume of 3 L, this is a sixty
times total plasma filtration.
The tubular secretion of water would mean that water is transported from the
peritubular capillary across the epithelial cells of the nephron into the lumen.
With a GFR of 180 L/day and normal urine production of around 1 % of GFR
(1.8 L/day), it is clear that no tubular secretion of water occurs in the kidneys (I
tell my students that if they still write “water is secreted and excreted”, their
grades will be immediately secreted!).
There is polyruia in glucosuria of diabetes mellitus. The increased water
excretion is due to the osmotic effect of unreabsorbed glucose at the proximal
tubules. The osmotic diuretic effect in glucosuria does not “attract, pull” or
drives water osmoactively into the lumen at the proximal tubules. In other
words, it is incorrect to say that unreabsorbed glucose causes water secretion at
the proximal tubule.
Rather, the excess glucose in the tubular fluid interferes and reduces the isoosmotic reabsorption of water at the proximal tubules. Normally ~ 70 % of total
glomerular filtrate is reabsorbed at the proximal tubules.
3. How do the water permeabilities of the loop of Henle in the renal medulla
contribute to a hyperosmotic interstitium?
Answer
The descending loop of Henle is permeable to water, the ascending loop is
always impermeable to water, and the collecting ducts become permeable to
always impermeable to water, and the collecting ducts become permeable to
water when the vasopressin acts.
Concept
The juxtamedullary (jm) nephrons together with their associated peritubular vasa
recta established and sustained a stratified hyperosmotic renal medulla. The jm
nephrons generate the hyperosmotic medullary interstitium (hmi) and the vasa
recta capillary blood flow preserves the hmi.
The reabsorption of water from the collecting ducts in the renal medulla requires the presence of two
factors; a hyperosmotic medullary interstitium generated by the renal countercurrent mechanism and
circulating vasopressin hormone from the posterior pituitary. In the renal cortex, only vasopressin alone is
available. The water is still absorbed at the cortical collecting ducts but limited by the iso-osmotic cortical
interstitium. Water from the hypotonic fluid that exits the loop of Henle will move out of the lumen when
the collecting ducts become water permeable by vasopressin’s action
The ability of the jm nephrons and the vasa recta to create the hmi is due to
the countercurrent flows in both the jm nephrons and the vasa recta. The tubular
fluid flow in countercurrent, and the vasa recta blood flow is also countercurrent
in the descending and ascending vasa recta. The student should not be misled by
the visual 2-D representation in physiology texts that often give the impression
that the countercurrent is between the tubular fluid flow in the nephron and the
blood flow in the vasa recta. The overall jm nephron/vasa recta renal machinery
that stratifies the medulla hyperosmotically is called the renal countercurrent
mechanism.
The jm nephrons have unique membrane water permeabilities at different
segments of the nephron. The descending fluid becomes increasingly
concentrated because the water is reabsorbed, but sodium, the major tubular
fluid solute is not reabsorbed. At the ascending loop of Henle (LoH), the
epithelial cell is unusual is not allowing water to transverse it, transcellularly and
even paracellularly. Sodium is reabsorbed here, actively at the thick segment of
the ascending LoH, transported by the triple Na/K/2Cl membrane carrier.
The hyperosmotic fluid (~ 1300 mOsm/L) that enters the ascending loop,
thus, becomes progressively diluted as it ascends and the fluid that exits the
ascending Loh is always hypotonic (~ 100 mOsm/L). The combined effects of
increasing sodium in the descending LoH and decreasing sodium in the
ascending LoH with extrusion of sodium dynamically produce a renal medulla
with increasing osmolarity, from 300 mOsm/L at the cortex to ~ 1300 mOsm/L
in the inner medulla.
The fate of the remaining filtrate that travels down the collecting ducts will
depend on the water balance in the body. In negative water balance, the ADH
(vasopressin) is secreted from the posterior pituitary and acts to make the
collecting ducts permeable to water. The availability of the hypertonic medullary
interstitium then osmoactively drives the water reabsorption.
4. What role of the vasa recta maintains the hyperosmotic renal medullary
interstitium?
Answer
The countercurrent vasa recta acts as a passive exchanger and maintains the
hyperosmotic interstitium by preserving the solutes in the medulla and removing
reabsorbed water from the medulla.
Concept
The juxtamedullary nephrons actively generate the hyperosmotic medullary
interstitium (hmi). The peritubular vasa recta capillaries that course along the jm
nephrons passively maintains the hmi. The countercurrent capillary blood flow is
essential to enable the vasa recta to fulfill this function.
Imagine swimming inside and down the descending vasa recta. Since the
vasa recta blood enters the renal medulla that is increasingly more hyperosmotic,
the passive movement of solutes enter the vasa recta, and the water exits the vasa
recta capillary into the interstitium. Thus, the blood at the tip of the vasa recta Utube will also equilibrate with its surrounding and become ~ 1300 mOsm/L.
As the hyperosmotic blood ascends the vasa recta, imagine again swimming
up and away into regions of the medulla with decreasing hyperosmolarity. The
solutes that entered previously during the descending blood flow will now
diffuse back into the medullary interstitium. Thus, little solutes are lost from the
renal medulla, and the hmi is preserved. This passive movement and
preservation of the hmi by the vasa recta is only possible, because the vasa recta
is a countercurrent structure. Otherwise, there will be “washout” effect of the
solutes by the descending capillary blood flow and the hmi cannot be sustained.
(The inquiring student may wonder at the exposure of the red cells to such
hypertonic blood in the vasa recta).
For water, the water that exits the descending vasa recta is returned in to the
ascending vasa recta as the capillary blood flows pass interstitium of decreasing
ascending vasa recta as the capillary blood flows pass interstitium of decreasing
hyperosmolarity. Again, we see that no water accumulates in the interstitium to
disrupt the hmi. The student should also note that the 2-D diagrams in textbook
may leave the impression that there are significant interstitial spaces between the
ascending and descending limbs of the vasa recta (and also the
ascending/descedign LoH). In reality, the two U-tubes (LoH and vasa recta) and
the collecting ducts (CD) are packed closely together (visualize a cross section
of the medulla as containing a closely associated group of five circles—two for
LoH, two for vasa recta, and one for the CD).
The ascending vasa recta also removes water that is reabsorbed at other parts
of the nephron. The descending LoH reabsorbs a smaller portion of the
glomerular filtrate (~ 20 %). The collecting ducts, under vasopressin action fine
tunes the degree of water reabsorption in response to changes in water balance.
Therefore, the water reabsorbed from the descending LoH and the CD also
enter the ascending vasa recta capillary and are carried away in the circulation.
The hmi remains highly hyperosmotic.
5. What is the contribution of urea to water excretion?
Answer
Urea contributes a major portion to the ability of the kidneys to produce the
maximum concentrated urine of ~ 1300 mOsm/L.
Concept
The highest osmolarity in the renal medulla is contributed by sodium chloride
and also urea. Urea is recycled from the inner medullary collecting ducts,
secreted into the LoH and circulates towards the CD again.
This recycling of urea between the CD and LoH occurs only when plasma
ADH level is increased. This is because ADH also increases the permeability of
the inner medullary CD to urea.
The hyperosmolarity in the medullary interstitium (hmi) will only be around
600–600 mOsm/L in the absence of urea recycling. In other words, during the
negative water balance when ADH is secreted, the hmi will be maximum at
~ 1300 mOsm/L.
The cortical CD are made permeable to water, but not urea. So urea is
concentrated along the CD. This allows urea to develop a concentration gradient
at the inner medullary CD from where it recycles when the membrane becomes
permeable to urea.
Conceptually, if the CD membrane is not made permeable to urea, the urea
will be osmoactive in the lumen and this will oppose water reabsorption when
the CD becomes permeable to water when ADH binds to the principal cells of
the CD becomes permeable to water when ADH binds to the principal cells of
the CD.
When secretion of ADH is inhibited during positive water balance, water
excretion is increased with a higher urine flow. The urea excretion rate (Uurea ×
V) is also increased during diuresis. During antidiuresis when water is
reabsorbed at the CD, the urine is concentrated and the urea concentration in
urine is also higher. But, the excreted urea load is lower than when the urine is
dilute and hypotonic, but the urine flow rate is larger.
When there is no recycling of urea during increased water excretion in the
biological absence of ADH, more urea is excreted in the urine.
6. What effects of a loop diuretic increase the water excretion?
Answer
Loop diuretic causes increased water excretion by inhibition of sodium
reabsorption at the LoH leading to a reduced osmotic gradient for water
reabsorption.
Concept
Loop diuretics inhibit the triple cotransporter Na/K/2Cl at the ascending LoH.
This secondary active transporter reabsorbs sodium and is a major contributing
mechanism that generates the hyperosmotically stratified renal medulla. The
hypertonic medullary interstitium (hmi) is essential to enable the kidneys to
concentrate urine during negative water balance.
By inhibiting loop transport of sodium, the hmi will be less hyperosmotic.
More sodium remains in the tubular fluid and increases the fluid osmoalrity. The
normal dilution of the fluid ascending the loop to produce “free water” no longer
occurs. Downstream at the collecting ducts, water is reabsorbed when the ducts
become permeable when acted upon by vasopressin secreted from the posterior
pituitary.
The osmotic gradient between the increased fluid osmoalrity in the collecting
ducts and the reduced hmi will be decreased. Even if the duct is permeable to
water, less water will be reabsorbed. Water excretion as the final urine volume
increases.
The effect of a loop diuretic can be said to cause an “osmotic dieresis,” since
it acts by osmotic interference.
Other categories of diuretics also inhibit sodium reabsorption and produce
similar effects in increasing water excretion. The sodium/chloride cotranporter at
the distal tubule is inhibited by the thiazide diuretics. The inhibitors of
aldosterone action at the principal cells of the collecting ducts will also result in
aldosterone action at the principal cells of the collecting ducts will also result in
unreabsorbed sodium in the lumen. An osmotic diuretic action is effected.
With aldosterone antagonists, there is no secondary loss of potassium in the
urine as occurs with loop diuretics. Action of loop diuretics alone leads to an
increase in tubular fluid that arrives “downstream” at the collecting ducts. The
principal cells respond to the increased sodium load by reabsorbing more
sodium. Since aldosterone also acts to promote potassium secretion at the same
target of principal cells, this results in hyperkaliuria and hence potential
hypokalemia.
7. How do the osmolarity and volume changes affect ADH secretion after
exercise loss of sweat?
Answer
Both the hyperosmolarity and the hypovolemia stimulate ADH secretion via
osmoreceptor and volume receptor pathway, respectively.
Concept
Sweat is a hypotonic fluid. In fact, sweat is designed to be always hypotonic.
Sweating results in a hypertonic contraction of the ECF. There is then a
compensatory shift of fluid from the cells to the ECF. Imagine if sweat is
hyperosmotic; the resulting hypotonic ECF will lead to more fluid shift into the
cells and further contracts the ECF! Sweat is, thus, wonderfully hypotonic.
Sweating results in both a negative water and negative sodium balance
(when body fluid is lost, there is always a negative sodium balance since all
body fluid contain sodium). The osmoreceptor/ADH mechanism is most
sensitive to ECF/plasma osmolarity changes. The hyperosmotic ECF will
stimulate ADH secretion. The ADH increases water reabsorption at the kidneys
to normalize the plasma osmolarity. Note that although the osmolarity is
restored, the sodium balance is still negative, until the fluid loss itself is
recovered.
The hypovolemia can also activate a reflex signal via the volume and
baroreceptors to increase ADH secretion. Hypovolemia concurrent with
hyperosmotic blood also increases the osm/ADH sensitivity.
As for ADH activation, the thirst neurons in the hypothalamus are also
stimulated by hyperosmotic ECF and hypovolemia.
The brain is involved in maintaining our water balance or osmoregulation. The thirst center neurons are
located in the hypothalamus. The hypothalamic osmoreceptors are associated with the posterior pituitary
secretion of the hypothalamic neurohormone vasopressin that increases the water reabsorption in the
kidneys. The micturition reflex for when we ‘Wee’ is coordinated by neurons in the brainstem and of course
voluntarily by our cerebral cortex
The complete normalization of ECF/blood volume will require the body to
respond to the negative sodium balance. This includes triggering sodium
conservating mechanisms which involve renin-angiotensin-aldosterone pathway
and increased renal sympathetic activity.
This triangle knowledge map links sodium balance with blood volume control by the kidneys. Note that this
is total body sodium and not sodium concentration (vasopressin controls the ECF sodium concentration).
Sodium balance is then physiologically associated with blood pressure. The renin-angiotensin-aldosterone
system (RAAS) regulates sodium/volume balance, not sodium concentration. Sodium balance changes are
thus monitored indirectly via volume/pressure vascular sensors
8. What is the relationship between osmolar clearance and free water clearance?
Answer
Osmolar clearance is equal to the urine flow rate for urine that is iso-osmotic to
plasma, and dilute urine will, thus, be the sum of osmolar clearance and free
plasma, and dilute urine will, thus, be the sum of osmolar clearance and free
water clearance.
Concept
The formula for osmolar clearance is the U × V/P ratio using osmotic
concentration instead of specific solute concentration. The U × V will then be
the excreted osmotic load and the P is the plasma osmolarity.
If the urine has the same osmolarity as plasma, the osmolar clearance will
then be just V, which is the urine flow rate in ml/min.
We can imagine dilute urine as consisting of a portion of iso-osmotic urine
and a portion of solute-free water (free water). Therefore, a dilute urine flow rate
V becomes the sum of the osmolar clearance C osm and the free water clearance,
C water .
Conversely, when concentrated urine is produced, the reduced urine flow can
be viewed as the C osm minus free water that has been reabsorbed. The latter is
also termed negative free water clearance.
The ascending LoH of the jm nephrons (same in cortical nephrons?)
reabsorbs sodium, but the membrane is impermeable to water (unique, unusual
property, which implies no membrane aquaporins and very tight intercellular
junctions). The tubular fluid that exits the ascending LoH is thus always
hypotonic. The ascending LoH is described as the “diluting segment” and the
reabsorption of sodium without accompanied water generates the free water. The
fate of this free water at the collecting ducts will depend on the water balance in
the body.
9. How does the ECF osmolarity and volume change in diabetes insipidus and
syndrome of inappropriate ADH (SIADH)?
Answer
In diabetes insipidus, the action of vasopressin (ADH) is reduced, resulting in
high volume dilute urine leading potentially to a hypertonic contraction. In
SIADH, uncontrolled, excessive ADH secretion leads to a hypotonic expansion.
Concept
In physiologic homeostasis, the ECF osmolarity is controlled by feedback inputs
from changing osmoalrity. Here, the fluctuation in osmoalrity is the cause and
the compensation mechanisms involving ADH and the kidneys the effectors.
In clinical situations, an abnormal secretion or action of ADH becomes the
primary cause, resulting in pathophysiologic effects on ECF volume and
osmoalarity. In some lung tumors that secrete ADH (SIADH; syndrome of
osmoalarity. In some lung tumors that secrete ADH (SIADH; syndrome of
inappropriate ADH), there is an excessive water reabsorption from the nephrons
independent of water balance in the body. There is retention of water and the
ECF is enlarged in a hypotonic expansion. The hypotonic ECF (hyponatremia)
can be life threatening as an excess water influx into neurons leads to brain
swelling. Neurological symptoms ensue.
Conversely, a defective hypothalamo-posterior pituitary neural linkage will
reduce the ADH secretion when needed. The kidneys cannot respond to negative
water balance or increased ECF osmolarity although the hypothalamic
osmoreceptors are stimulated. The kidneys continue to excrete a hypotonic
large-volume urine. The hypertonic contraction of the ECF is not compensated
for by the kidneys. However, a conscious person will have a greater thirst to
drink as the hypertonic ECF will stimulate the thirst neurons also present in the
hypothalamus. The plasm osmolarity in a diabetic insipidus person could, thus,
be normal due to the increased water intake.
Note the increased water excretion in diabetes insipidus (DI) is due to little
ADH action (can be receptor dysfunction in nephrogenic DI) while the polyuria
in diabetes mellitus is produced by the osmotic diuresis that accompanies
glucosuria. The dehydration in diabetes mellitus if the diuresis is high will
stimulate ADH secretion since the hypothalamus is normal as pancreatic insulin
is the problem.
10. How are the cortical nephrons involved in water balance?
Answer
The cortical nephrons also reabsorb water as they share the same colllecting
ducts with the juxtamedullary nephrons.
Concept
The ability of the kidneys to produce concentrated urine is important during
negative water balance, e.g., dehydration from sweating. The subpopulation of
jm nephrons are dedicated to generating a hyperosmotic interstitium which
enables the kidneys to concentrate urine during reabsorption of water.
The jm nephrons is less than 20 % of the total nephron population. The
glomerular filtration rate is a combined value from every nephron in both
kidneys. Thus, although the jm nephrons are the focus when describing the
kidneys’ unique ability to concentrate urine, the student should not forget that
the crotical nephrons together contribute at least 80 % of the remaining filtrate
that enters the collecting ducts.
If there is a positive water balance, the hypothalamic osmoreceptors are
If there is a positive water balance, the hypothalamic osmoreceptors are
inhibited and ADH secretion is suppressed. ADH increases the permeability of
the collecting ducts in both the cortex and medulla of the kidneys. In the absence
of the ADH, the cortical and meduallry ducts are impermeable to water. The
urine that exits the collecting ducts from the cortical and jm nephrons is
hypotonic and large in volume.
In negative water balance, the cortical collecting ducts are permeable to
water when acted by ADH. The tubular fluid is reabsorbed until osmotic
equilibrium is reached at 300 mOsm/L, the value of the osmoalrity in the
cortical insterstitium. Remember that the fluid that flows from the LoH is always
hypotonic due to the “diluting segment” of the ascending LoH that generates the
“free water”. Further water reabsorption from the collecting ducts proceeds at
the renal medulla. The maximum hyperosmotic human urine is set by the highest
strata of interstitial osmolarity in the inner medulla which is 1300 mOsm/L.
A normal 1 % of GFR excreted as urine is 1.8 L/day. The urine volume can,
thus, vary in response to water balance. The urine osmolarity, likewise, varies
from a very dilute 50 mOsm/L to 1300 mOsm/L.
© Springer International Publishing Switzerland 2015
Hwee Ming Cheng, Physiology Question-Based Learning, DOI 10.1007/978-3-319-12790-3_15
15. Sodium Balance
Hwee Ming Cheng1
(1) Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
Hwee Ming Cheng Email: chenghm@ummc.edu.my
The cation sodium is the predominant solute in the extracellular fluid (ECF). The
concentration of sodium in the ECF is tenfold higher than inside all cells. The
sodium cation together with its associated anions (“comp Anions”) are the main
determinants of ECF osmolarity. This electrolyte profile explains why total body
sodium (sodium balance) determines the volume of the body fluid compartment
of ECF.
The homeostatic control of ECF volume is thus tightly linked to the
regulation of sodium balance. The student should give attention to the different
set of homeostatic factors that govern ECF sodium concentration which are not
identical to effectors that control ECF sodium balance.
Since the ECF and blood volume are determinants of blood pressure,
mechanisms that involve renal functions in ECF volume and sodium balance are
part of the overall, integrated physiology of blood pressure regulation. The
kidneys excrete urine containing varying sodium and water load. The urinary
excretion of sodium is a controlled event and tied to blood volume/pressure
maintenance. Just remember this urinary effector of the kidneys’ role in blood
pressure (BP) as BPee!
The heart protects itself from being overloaded with fluid, i.e.,
overcongestion when blood volume expands. The cardiac chambers have
mechano-volume receptors that monitor the “fullness” of the systemic vascular
compartment. This is related to maintaining an optima central venous or right
atrial pressure for normal circulatory venous return. The cardiac muscle also
secrete a natriuretic hormone that acts on the kidneys to produce natriuresis,
which is increased urinary sodium and water excretion.
which is increased urinary sodium and water excretion.
Sodium is thus “so-dium” important in the reno-cardiovascular homeostasis
of ECF volume which affects blood volume and pressure.
1. What common membrane protein reabsorbs sodium at the proximal tubule
and the loop of Henle?
Answer
The sodium/potassium ATPase is present at both the basolateral membrane of
the proximal epithelial and loop endothelial cells, and this ATPase actively
drives the transepithelial sodium reabsorption.
Concept
Filtered sodium is on average 99 % recovered or recycled into the peritubular
circulation. The sodium is predominantly reabsorbed transepithelially along the
nephron. Some sodium can diffuse through the tight intercellular junctions from
the lumen to the interstitium. The entry of tubular fluid sodium into the cells
uses different transporters at the luminal membrane. From inside the cells, the
extrusion of sodium across the basolateral membrane into the renal interstitium
employs the same ubiquitous Na/K ATPase pump.
At the proximal tubule, sodium enters the epithelial cells mainly through
coupled transport with solute. This includes the familiar sodium-glucose
cotransporter, amino acid-sodium symporter. A major luminal membrane
exchanger, the Na/H antiporter also brings sodium into the cell.
At the thick ascending loop of Henle, the luminal sodium transporter is
coupled to two other ions—chloride and potassium. We can correctly view this
transporter as a component of the sodium-linked, secondary active transport of
chloride and potassium.
At the distal tubule, we have a sodium-chloride cotransporter, and this
membrane protein is the target site for the thiazide diuretics.
The sodium reabsorption at the principal cells of the collecting ducts is under
hormonal regulation by the steroid, aldosterone. Here, sodium enters the
principal cell via sodium channels at the luminal membrane. These membrane
sodium channels are upregulated by aldosterone action. The basolateral
membrane Na/K ATPase then completes the second step of transcellular sodium
reabsorption.
The adrenal gland (triangle!)secretes mineralocorticoids, steroid hormones, the chief species being
aldosterone. Aldosterone is the key hormonal regulator for both potassium and sodium homeostasis. The
action of aldosterone is for both K+ and Na+ balance, at the target principal cells of the collecting duct.
Changes in ECF K+ is directly sensed by the adrenal cortex while sodium imbalance is detected via a
change in blood volume/pressure
The luminal sodium channels at the principal cells can be inhibited by drugs
like amiloride and triamterene. These agents that obstruct the sodium channels
are potassium-sparing diuretics, since they act on the principal cell (same cell
that secreted potassium) and not “upstream” like the loop diuretics which has
kaliuric side effects.
2. How are the movements for sodium and water related, if in any way, along the
juxtamedullary nephrons?
Answer
Due to the unique differential permeability to sodium and water along the
juxtamedullary nephrons, water follows sodium reabsorption only at the
proximal tubule.
Concept
Water moves only when there is an available osmotic gradient. Along the
juxtamedullary (jm) nephrons, the osmotic gradients are set up in different ways.
At the proximal tubule, water is reabsorbed iso-osmotically following
sodium/solute reabsorption. The latter generates the local osmotic transepithelial
gradient for water to move transcellularly via aquaporins or paracellularly.
Osmotic force is the universal driving pressure for water movement throughout the body and certainly in
the kidneys. Whenever an osmotic gradient is present or generated (different mechanisms operating at
various sites), water will naturally move from the region of lower effective osmolarity (osmotic pressure)
across a selectively permeable physiologic barrier (e.g., membrane, capillary wall) to the higher osmotic
mmHg
The renal medullary interstitium is uniquely hyperosmotic due to the renal
countercurrent mechanism involving the jm nephrons and the associated
peritubular vasa recta capillary. At the descending loop of Henle (LoH), the
membrane is not permeable to sodium. Water alone is reabsorbed osmotically,
driven by the hypertonic interstitium surrounding the descending loops.
At the ascending LoH, the membrane is unusual in being permanently
impermeable to water. Sodium is, however, reabsorbed at the ascending LoH,
passively at the thin segment and actively at the thick segment by the Na/K/2Cl
cotransporter. The water remaining in lumen becomes progressively diluted and
hypotonic, as it ascends the LoH.
The collecting ducts (also for the cortical nephrons) have changing
permeability to water depending on the presence of the circulating hormone
vasopressin which exits the vasa recta to bind to receptors on the basolateral
membrane of the principal cells. Vasopressin stimulates the insertion of more
aquaporins at the luminal membrane. Here again, the reabsorption of water is
driven by the hyperosmotic interstitium as it occurs at the descending LoH.
Thus, in summary, if we imagine a cartoon of water molecule talking to
sodium cation, the speech will be; at the proximal tubule, “I, water will follow
you, Sodium.” At the descending LoH, “You, Sodium can’t follow me.” At the
ascending LoH, “I can’t follow you, Sodium.”
3. Do the renal tubules secrete sodium?
Answer
Answer
There is no transepithelial secretion of sodium by the nephrons.
Concept
The renal handling of sodium is excretion = filtration minus reabsorption. There
is no transcellular active secretion of sodium by the epithelial cells along the
nephron. In positive sodium balance, the kidneys compensate by decreasing
sodium reabsorption. This leads to an increased sodium excretion.
What about passive secretion of sodium via the paracellular route? Quite
certainly in the cortical nephrons, this should not be an event. This is, because
there is no concentration gradient between the cortical interstitium and the
tubular fluid.
At the proximal tubule (both cortical and jm nephrons), the surrounding
tissue is the cortex which is iso-osmotic to plasma. The sodium reabsorption
here is actually a net effect of transepithelial sodium movement and some back
leak of sodium from the interstitial fluid into the lumen via the tight junctions.
Normally, this back flux of sodium is minimum as water is reabsorbed isoosmotically at the early proximal segment. Thus, the tubular fluid is still isoosmotic to the interstitium. In glucosuria of diabetes mellitus, an osmotic
diuresis results. Not only is water excretion increased as polyuria, there is also
loss of sodium. This is due to the effect of unreabsorbed glucose in reducing the
net sodium reabsorption. The back leak of sodium becomes significant, since
water reabsorption at the proximal tubule is decreased due to the osmoactive
glucose in glucosuria. The sodium concentration in the tubular fluid is then
diluted and a sodium concentration gradient for passive sodium flux into the
tubular fluid exist.
In the juxtamedullary nephrons, the LoH and the collecting ducts are
surrounded by the osmotically stratified hypertonic renal medulla. At the
ascending LoH, sodium is reabsorbed, and this sodium movement contributes to
the generation of the hypertonic interstitium. At the descending LoH, we can
expect some passive diffusion of sodium from the hyperosmotic interstitium
paracellularly into the tubular fluid.
4. In hypertonic contraction, what parameter(s) activate the homeostatic
mechanism for sodium balance control?
Answer
The decreased volume stimulate sodium conservating mechanisms in order to
restore the fluid volume lost.
Concept
When you lose sweat, you are in both negative water and negative sodium
balance. Sweat is a hypotonic fluid, but sodium is still lost in the perspiration.
ECF volume is determined by the total body sodium (sodium balance).
In order to recover fluid volume, the loss of sodium has to be replaced. The
kidneys will excrete less sodium. The mechanisms linking hypovolemia to
decreased urinary sodium excretion involve the body sensing the volume
reduction.
Three sets of volume sensors are operative—the high pressure arterial
baroreceptors (carotid, aortic sinus), the volume receptors at the venous side,
including the atria wall and pulmonary vasculature. In the kidneys the intrarenal
baroreceptors sense the renal arterial pressure, which will be decreased with
hypovolemia.
Renal sympathetic nerve (RSN) action conserves ECF/blood volume. This is effected as the RSN
vasoconstriction decreases glomerular filtration rate (GFR). The filtered sodium and water are reduced. The
RSN also increases renal tubular sodium reabsorption directly and also via stimulation of renin release. The
RSN is also a part of the arterial blood pressure control effectors via renal arteriolar constriction, which
raises the TPR
Note that the hypernatremia from sweating is not the parameter that will
signal for sodium conservation. If it is, then the body should reduce sodium
retention in order to respond to the hypernatremia. The negative sodium balance
occurs as a result of lost body fluid, and all fluids contain sodium to varying
extent.
The sensing of hypernatremia actually is by the hypothalamic osmoreceptors,
since the sodium concentration is the main determinant of ECF osmolarity.
Thus, the antidiuretic hormone (ADH) secretion will increase to help in restoring
the water lost. But, the complete recovery to normal ECF volume will require
the return of the total body sodium to normal.
Excretion of sodium is the filtered load minus reabsorbed sodium.
When the volume sensors detect hypovolemia/hypotension, the
compensatory reduction in excreted sodium will be effected by decreasing
filtered sodium and at the same time, increasing renal sodium reabsorption. The
two major effectors that link volume sensing to urinary excretion of sodium are a
nerve and a family of hormones. They are the renal sympathetic nerve and the
renin-angiotensin-aldosterone “so-dium” conservative party (or phyarty in
physiology)!
Renin. Three strokes to write the letter R. Three “stimulus strokes” affect renin secretion from the
juxtaglomerular cells of the afferent arteriole: renal sympathetic nerve, renal arterial/perfusion pressure, and
paracrine signal from macula densa
5. In high sodium diet, what hormone action help to restore sodium balance?
Answer
Natriuretic hormones are called into play to promote urinary excretion of
sodium.
Concept
A high sodium diet will lead to an expansion of the ECF volume. This is
mediated by osmoreceptor/ADH mechanism and the thirst sensation. Because
the osmoregulation is a rapid-responding feedback, the final equilibrium
observed with a high sodium diet is an increased ECF volume rather than an
increased ECF osmolarity.
With a high sodium diet, an initial hypertonic expansion (intracellular fluid
(ICF)/ECF shift before ADH acts) will lead eventually to an isotonic expansion
(after osmoregulation with ADH). This sequential explanation is helpful, but the
student should note that the ICF to ECF fluid shift and ADH action overlap and
occur dynamically.
An enlarged ECF volume will be detected by the various volume/pressure
sensors. A general decrease in sympathetic activity including renal sympathetic
input to the kidneys is a major compensation. Sodium excretion is enhanced.
In addition, volume sensors in the heart detect the increased vascular fullness
and release atrial natriuretic peptide (ANP). This ANP is now part of a family of
hormones including brain natriuretic peptide and the renal paracrine, urodilatin
that, as the name suggest acts to increase both sodium and water excretion.
Circulating natriuretic hormones thus have opposing actions to aldosterone
and ADH. In fact, the ANP has been shown to inhibit both aldosterone and ADH
secretion. It likely also inhibits the renin release from afferent arteriolar
juxtaglomerular (JG) cells in addition to the effect of reduced sympathetic
stimulation on JG cells.
It can be reasoned that natiruretic hormones, including the paracrine
urodilatin will increase the filtered load of sodium in order to increase sodium
excretion. This is achieved as natriuretic hormones vasodilate the renal
arterioles. The renal blood flow and hence the GFR is higher, producing the
greater filtered sodium load.
6. How does renal sympathetic direct, nonhormonal actions on renal structures
affect sodium excretion?
affect sodium excretion?
Answer
The renal sympathetic nerve acts on the proximal tubule to increase the sodium
reabsorption and on vasoconstricting the renal arterioles to decrease filtered
sodium load.
Concept
The more familiar action of renal sympathetic nerve (RSN) on renal handling of
sodium to students perhaps is the effect on the arteriolar granular JG cells to
secrete renin.
RSN conserves sodium. This autonomic nerve is sympathetic to sodium!
In other words, RSN decreases urinary sodium excretion. This is mediated
by both reducing the filtered sodium load plus increasing renal sodium
reabsorption. The renal arterioles are both constricted by the RSN. The renal
blood/plasma flow is decreased, and GFR and hence filtered sodium load are
lowered.
Concurrently, the proximal tubular epithelial cells are innervated by fibers of
sympathetic nerve. Release of sympathetic neurotransmitter onto the proximal
tubules stimulate sodium reabsorption.
The student may recall that when the intrinsic glomerulo-tubular (g-t)
balance was described, the mechanism does not include the involvement of any
extrinsic nerve or hormone action. In g-t balance, increase/decrease in GFR is
compensated by a corresponding increase/decrease in proximal tubular
reabsorption of sodium and water.
However, when the renal sympathetic nerve activity is high, the g-t balanced
is overrided and pushed to the physiologic background. The RSN reduces GFR,
but increases the proximal tubular reabsorptive function.
This occurs during negative sodium balance or hypovolemia and the
physiologic priority to restore sodium/volume now is given over to the actions of
RSN over g-t balance.
7. How is the macula densa involved in sodium balance?
Answer
The macula densa has a paracrine signal that increases renin release from the
afferent arteriolar JG cells.
Concept
In the series of renal lectures, the macula densa (McD) is described as part of the
juxtaglomerular apparatus (JGA) in effecting renal autoregulation of renal blood
juxtaglomerular apparatus (JGA) in effecting renal autoregulation of renal blood
flow/GFR. In renal autoregulation, the paracrine from the McD is a
vasoconstrictor that alters the vascular resistance of the preglomerular afferent
arteriole.
The McD has a second role in renal functions and this is in the regulation of
sodium balance. The second paracrine mediator from the McD modulates the
secretion of renin from the JG cells. This McD paracrine renin stimulator(s)
would be active when the person is in negative sodium balance of
hypovolemia/hypotension. Renin then activates the generation of angiotensin II
(AII), a potent vasoconstrictor and the trigger for aldosterone release from the
adrenal glands.
Note that in the same situation, e.g., the hypovolemia which will reduce renal
blood flow, the expected autoregulatory response should be vasodilation of the
afferent arteriole. Thus, by physiologic deduction, the renin is not involved in
renal autoregulation since the AII that is derived from renin activationwill
constrict the renal arterioles.
One could infer that the second sodium balance homeostatic signal of the
McD is a more dominant paracrine than the paracrine that effects autoregulation.
The McD signal that releases renin from JG cell always works cooperatively
and in concert with the other two inputs that affect JG cell renin secretion. These
are the renal sympathetic nerve and the intrarenal baroreceptors (these
volume/pressure sensors might be a structural component of the JG cells or a
peri-JG cell receptor).
8. After drinking isotonic saline, how is sodium and water excretion affected?
Answer
With the isotonic expansion, the sodium excretion is increased gradually,
accompanied by water excretion. There is no peaked natriuresis.
Concept
Some students in renal laboratory practical enlist a volunteer to drink several
hundred ml of isotonic saline (how much depends on weight of student) in a
short time. Then urine samples are collected every 30 min and measured for
water and sodium excretion.
The subject will be in both positive sodium and positive water balance.
There is no observable water diuresis that is due to the inhibition of ADH
secretion. The isotonic ECF will not affect ADH secretion, but the increased
ECF/vascular volume will inhibit ADH. Since there is no observed evidence of a
peak water excretion, inhibition of ADH cannot explain how the body will
peak water excretion, inhibition of ADH cannot explain how the body will
succeed in eliminating the excess water in urine. Imagine if the hypervolemia
does initially inhibit ADH, any initial increased in water excretion will elevate
the ECF osmolarity and this will begin to stimulate ADH and oppose the
hypervolemic suppressing effect on ADH.
The positive sodium balance with the hypervolemia is dealt with by
increasing sodium excretion. As sodium excretion increases over several hours,
then water excretion will follow as osmoregulation also kicks in. The gradual
compensatory response in excreting sodium reflects the time taken for reducing
the plasma levels of the hormones in the renin-angiotensin-aldosterone family.
A decrease in renal sympathetic action due to hypervolemia-baroreflex
feedback response also plays a part in promoting sodium urinary excretion.
9. How might renal atherosclerosis affect arterial blood pressure?
Answer
The renal artery stenosis leads to hypersecretion of renin and hypertension
Concept
The intrarenal baroreceptors respond to changes in renal arterial pressure. If they
sense a reduction in the renal perfusion pressure, they will activate the JG cells
to secrete renin. A reduction in vascular volume in blood volume loss will
provoke the intrarenal baroreceptors to increase the renin secretion.
If the blood volume is normal, narrowing of the renal artery can also
decrease the downstream renal perfusion pressure. This renal stenosis can be due
to atherosclerotic vascular tissue growth. The resultant increase in renin will
produce increased plasma angiotesin II and aldosterone.
Sodium and water retention will occur due to the combined renal actions of
both aldosterone and AII. The hypervolemia will give a greater cardiac output, a
determinant of arterial blood pressure.
AII is a strong vasoconstrictor. The total peripheral resistance, the other
determinant of blood pressure, will be raised and this elevates the arterial blood
pressure.
The unregulated secretion of renin in renal arterial stenosis will continue as
long as the renal baroreceptors keep sensing the low renal perfusion pressure.
The expanded ECF/blood volume will decrease the renal sympathetic
stimulation of the JG cells. However, JG cells will still be “poked” by the low
pressure at the afferent arteriole and also by positive signals from the macula
densa. The decrease in renal blood flow due to the stenosis will lower the GFR
and the volume of tubular fluid arriving at the distal tubular macula densa.
Secretion of natriuretic hormones as a result of the vascular congestion may
Secretion of natriuretic hormones as a result of the vascular congestion may
provide some “aldosterone escape” effect to counteract the retention of sodium
and water.
10. How is sodium balance altered in primary hyperaldosteronism?
Answer
The positive sodium balance and expansion of the ECF volume inhibits renin
secretion from the kidneys.
Concept
In normal persons, the activation of hormonal stimulation of sodium
conservation stars with renin. The “once upon a time” begins with renin release.
In the pathophysiologic situation of a hypersecreting adrenal tumour of the
glomerulosa cells (Conn’s syndrome), sodium retention occurs in an unregulated
manner.
ECF volume and blood volume will expand. The increase in cardiac output
elevates the arterial blood pressure. The three (can the students recall from the
previous questions?!) inputs that impinge on the JG cells to stimulate renin
secretion are halted. Plasma renin concentration is reduced. So in Conn’s
syndrome, the “once upon a time” begins with high aldosterone secretion.
This causes the feedback inhibition of renin secretion from the JG cells.
The excess plasma aldosterone would also increase the loss of potassium in
the urine with increased potassium secretion. Hypokalemia is an associated
problem.
In the opposite endocrine condition of primary adrenal insufficiency
(Addison’s disease; deficiency or “minus” all adrenal corticosteroid hormones in
this “Add” disease!), the mineralocorticoid aldosterone is severely lacking. The
ECF will eventually be hypotonically contracted. This ECF status is not possible
in a normal person with functioning osmoregualtion. Loss of sodium in the
absence of aldosterone leads to a marked reduction in blood volume. This initial
isotonic contraction will progress to a hypotonic contraction, when the
hypovolemia becomes critical.
At this stage, the priority in maintaining a sufficient blood volume to sustain
blood perfusion becomes more essential than osmoregulation. The threshold
point for water reabsorption by the osmoreceptor/ADH mechanism is reset to a
lower plasma osmolarity. This osmostat change is to allow more water to be
reabsorbed before the ADH secretion is inhibited again.
Part IV
Cardio-Respi-Renal Physiology
© Springer International Publishing Switzerland 2015
Hwee Ming Cheng, Physiology Question-Based Learning, DOI 10.1007/978-3-319-12790-3_16
16. Cardiorespiratory Physiology
Hwee Ming Cheng1
(1) Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
Hwee Ming Cheng Email: chenghm@ummc.edu.my
What did Cardio say to Respi? “You provide the gas, I will provide the
transport!” Cardiovascular physiology is appropriately taught before respiratory
physiology in a well-designed undergraduate curriculum. We always teach the
general before mentioning the exceptions. Pulmonary hemodynamics have their
own unique functional characteristics, different from systemic control of arterial
blood pressure and regional organ flow.
The cardiorespiratory integrated role is to provide well-oxygenated blood for
tissues to match changing metabolic demands at rest or during physical
activities. Metabolic carbon dioxide is also conveyed through blood to the lungs
to be expelled. Blood CO2, however, is not merely a metabolic waste.
Blood/extracellular fluid pH is regulated through the essential function of
alveolar ventilation/chemoreceptor sensing/CO2 mechanisms.
1. How does the hemodynamic relationship, Flow = P/R in the pulmonary
circulation compare with the systemic circulation?
Answer
The pulmonary flow rate is the same as the left ventricular output. The right
ventricular moderate systolic pressure is matched by a lower pulmonary vascular
resistance.
Concept
The systemic and pulmonary circulations are in a circuit in a closed
cardiovascular system. The left ventricular systolic pressure has a high
maximum of 120 mmHg to propel blood into the periphery. The right ventricle is
less muscular and need only generate an intraventricular pressure of ~ 30 mmHg
to provide the right ventricular cardiac output.
This leads to the obvious derived fact that the pulmonary vascular resistance
(pulmonary vascular resistance, pvr, is significantly less than the systemic “total
peripherial resistance (TPR).”
There are also different cause and effect mechanisms between the pulmonary
and systemic hemodynamics. In the systemic circuit, the blood pressure is
determined by the two parameters cardiac output (CO) and TPR. Changes in CO
and/or TPR are involved in the compensatory responses to maintain blood
pressure. In other words, the relationship is a right to left direction.
In contrast, in the pulmonary circulation, the pvr is mechanically affected by
the pulmonary arterial pressure because the pulmonary vessels are relatively
compliant. When the right ventricles eject a greater stroke volume, the raised
pulmonary arterial pressure distends the pulmonary blood vessels. Besides
vascular distention, the increased pulmonary blood pressure also recruits more
underperfused, relatively nonpatent vessels at rest.
Thus, in pulmonary hemodynamics, the mechanistic pathway is from left to
right
This unique feature of the pulmonary vascular explains why the pulmonary
arterial pressure does not rise very much when the cardiac function increases
during physical activity (note this reason is actually a right to left cause and
effect).
The CO2 ClO2ckwise. Venous PCO2 is the same as tissue PCO2 (46 mmHg) as deoxygenated blood has
equilibrated with metabolic CO2 in cells. At the lungs, the removal of CO2 by diffusion and alveolar
ventilation returns the PCO2 in arterial blood to that of alveolar air (40 mmHg)
2. Compare the rate of pacemaker action potential activity in heart and lungs and
2. Compare the rate of pacemaker action potential activity in heart and lungs and
the muscle type stimulated.
Answer
The cardiac atrial pacemaker cells emit action potentials at a rate of
~ 70 times/min. The respiratory “pacemaker” neurons generate action potential
to the skeletal respiratory muscles at a rate ~ 10–12 times/min.
Concept
The cardiac specialized cells at the right atrium spontaneously generate action
potentials (AP) that are then transmitted to the rest of the myocardium. The
inherent rate of AP production is modulated by inputs from both the
parasympathetic and sympathetic nerves. The resting heart rate is dominated
more by the vagal parasympathetic tone.
Normal respiratory rate is set by the spontaneous AP generating neurons in
the brain stem. The impulses are conveyed to motor neurons that supply the
inspiratory muscles of the lungs. Inspiration is an active muscle contraction
event. Normal expiration begins with the cessation of the AP and the chest wall
and elastic lungs recoil passively.
The skeletal muscles of inspiration are involved during voluntary
hyperventilation. The initiating impulse originates from the cortical areas of the
brain and it is transmittted directly to the respiratory skeletal muscles, bypassing
the rhythmic regulatory neurons at the brain stem that sets the resting tidal
volume and breathing frequency.
When one holds her breath, the inhibitory cortical impulses must be
suppressing the autorhythmic signals from the brain stem to the respiratory
muscles.
3. How does the driving perfusion pressure for pulmonary blood flow compare
at the apex and base of the lung?
Answer
The arterial-venous driving pressure at each level of the upright lung is the same
since gravity affects both the hydrostatic pressure at both the arteries and veins.
Concept
The gravity affects the distribution of the right heart cardiac output to the upright
lung. The pulmonary blood flow is more to the base of the lungs and
progressively decreases vertically to the apex.
This reduction in blood flow to the apex of the upright lungs is not due to
any drop in the arterial-venous perfusion pressure. The hydrostatic pressure in
any drop in the arterial-venous perfusion pressure. The hydrostatic pressure in
both the arteries and the veins decreases proportionately above the level of the
heart.
The resistance to pulmonary blood flow in the lungs is also modified by the
intraalveolar pressure (PA) that exerts a mechanical compression on the alveolar
capillaries. The upright lungs is divided into three zones based on the essential
driving pressure for blood flow that is operative at the different zones.
In the bottom third of the lungs (zone 3), the perfusing pressure is the arterial
(Pa)-venous pressure (Pv) difference. Thus, here Pa > Pv > PA.
In the middle third of the lungs (zone 2), the arterial pressure is greater than
the alveolar air pressure which is now a pressure that exceeds the venous
pressure Here, Pa > PA > Pv. The driving perfusing pressure is between the
pulmonary arterial blood and the alveolar air pressure.
In the upper third of the lungs (zone 1), the alveolar air pressure can exceed
the reduced arterial pressure and occlude the pulmonary blood flow The
determining pressure difference that defines blood flow to the apex of the lungs
is the PA > Pa.
If arterial pressure is decreased due to hypovolemia or if the alveolar air
pressure is increased as in positive pressure breathing, then the alveoli in Zone 1
will be ventilated by not perfused. These alveoli in these conditions no longer
participate in gas exchange; they have a ventilation/perfusion (V/Q) ratio of
infinity (Q = zero) and represent abnormal alveolar “dead” spaces.
4. Why does the pulmonary vascular resistance change during a respirator cycle?
Alveolar, extraalveolar vessels.
Answer
The total pulmonary vascular resistance (pvr) is the sum of the vascular
resistances at the alveolar and extraalveolar capillaries. The resistances of the
two segments of pulmonary capillaries are differently affected by intrathoracic
and intraalveolar air pressure changes during a respiratory cycle.
Concept
Obviously the systemic total peripheral resistance (TPR) does not change during
a respiratory cycle. The vascular radius of the pulmonary vessels, however, is
affected by respiratory pressure changes during a breathing cycle.
The pulmonary capillaries that enmesh the alveoli are subject to the alveolar
air pressure that opposes the intravascular pressure. Thus, with increasing lung
volumes, the more expanded alveoli will compress and mechanically increase
the vascular resistance.
the vascular resistance.
In contrast, with inspiration, the intrathoracic pressure decreases. The radius
of the extraalveolar blood vessels are affected by the transmural pressure which
now involves the intrathoracic pressure outside the extraalveolar vessels. A deep
inspiration will increase the transmural pressure and distend and lower the
vascular resistance.
Thus, inspiration is associated with a relative higher resistance in the alveolar
and a lower resistance in the extraalveolar pulmonary blood vessels. And in
expiration, the resistance in the alveolar vessels becomes less and is now higher
at the extraalveolar vessels.
The net change in vascular resistance during a respiratory cycle sums up to a
lowest pvr at the end of normal expiration, at functional residual capacity (FRC).
The pvr changes in a U-shape profile, where below and above FRC, the pvr
increases with decreasing and increasing lung volumes, respectively.
5. In the upright lung, how does the partial pressure of oxygen and blood
oxygenation at the apex compare with the base of the lung? V/Q high apex, but
oxygenation more at base.
Answer
Although the partial pressure of oxygen is higher at the apex of the upright lung,
the net oxygenation is still better at the base of the lung, where pulmonary
perfusion is more.
Concept
The partial pressure of both oxygen (PO2) and carbon dioxide (PCO2) in the
alveoli is not merely due to the alveolar ventilation but rather to the matched
V/Q balance. In the upright lung, the V/Q matching varies from less than 0.8
(0.6) at the base of the lungs to more than 0.8 (3.0) at the apex of the lungs. The
value 0.8 is the overall V/Q of the whole lungs with alveolar ventilation at
4 L/min and pulmonary blood flow at 5 L/min.
The partial pressure of alveolar air is determined by two events; rate of cellular CO2 production (VCO2)
and the rate of alveolar ventilation. If VCO2 is constant at rest, a voluntary hyperventilation will decrease
the alveolar PCO2. A respiratory alkalosis with hypocapnia is produced
A higher V/Q at the apical alveoli means that they are relatively
overventilated. As such, these alveoli will have a higher PO2 (> 100 mmHg,
~ 130 mmHg) and a lower PCO2 (< 40 mmHg, ~ 30 mmHg).
However, when we look at actual oxygenation of the pulmonary blood, the
relatively underventilated alveoli at the base of the upright lungs are still better
off. The alveolar PO2 at the base of the lungs is about 90 mmHg.
The cooperative association of hemoglobin for oxygen means that at
90 mmHg, the blood oxygen saturation of hemoglobin will only be little
affected. And, since the oxygenation is perfusion limited, the better blood flow
to the base of the lungs results in greater oxygenation.
The difference between basal and apical lung oxygenation is minimized
during physical activity when the cardiac output is increased. The perfusion to
the apex of the lungs is improved. The apical alveolar V/Q will be less than that
at rest, but the oxygenation of the pulmonary capillary blood will be better.
The alveolar ventilation (V) and the pulmonary blood perfusion (Q) decrease from the base to the apex of
the upright lung. The overall V/Q of the whole lung is 4 or 5 L/min, giving 0.8. Since the reduction in Q is
more pronounced than for V, the V/Q ratio increases from the basal to the apical zones
6. At an intrapulmonary shunt, how will the alveolar air partial pressure of O2
and CO2 change? Alveolar dead space.
Answer
At an alveolar shunt, the V/Q ratio is zero, meaning the alveolus is unventilated.
The partial pressure of the respiratory gases will resemble that in the mixed
venous blood, i.e., for oxygen 40 mmHg and for CO2, 46 mmHg.
Concept
Concept
There are a variety of shunts, the term used for both normal and abnormal
cardiorespiratory physiology. In normal physiologic shunt, this refers to the
slight mixing of shunted, deoxygenated blood with the main bulk of oxygenated
blood from the alveoli. This normal admixture lowers marginally the partial
pressure of O2 in the arterial blood (< 15 mmHg) from the blood that leaves the
alveoli (~ 103 mmHg).
This physiologic shunt includes part of the bronchial blood and the blood in
some of the small cardiac Thebesian veins that drain directly into the left
ventricle, bypassing the lungs.
Thus, a physiologic shunt is due to anatomic architecture!. Clinically, when
an “anatomical shunt” is named, it represents an excess of deoxygenated blood
mixing with arterialized blood from the lungs. The classic example is a right to
left shunt that is due to intracardiac septal defect. Not all the venous blood is
delivered to the lungs to be reoxygenated. The portion that short-circuited from
the right to the left atrium will dilute the PO2 of blood that is pumped out by the
left ventricle.
An intrapulmonary shunt, due to blockage of some airway passages, the
affected alveoli are not ventilated (V = zero). The alveoli are not replenished
with new, fresh inspired air. Eventually, the alveolar air at the end of the
occluded airways will equilibrate with the partial pressures of the gases in mixed
venous blood PO2, 40 mmHg and PCO2, 46 mmHg.
Alveolar “dead space” in contrast occurs when there is a pulmonary embolus
to a region of the lungs. The affected alveoli have very high V/Q ratio (infinity
as perfusion is zero). Since no removal of oxygen from or release of CO2 into
the alveoli take place, the unperfused alveoli will only be ventilated and the
alveolar air partial pressures of O2/CO2 will approach that of inspired air.
7. Does hyperventilation contribute mainly to the increase in oxygen
requirement by cells during exercise? Co x oxygen content sigmoid perfusion
limited.
Answer
The increased pulmonary blood flow is the main contributor to the greater
oxygen delivery rate to the cells. The hyperventilation, instead, has the essential
role in the removal of metabolic carbon dioxide during exercise.
The rate of oxygen delivery to tissues is equal to the product of the arterial oxygen blood content and the
cardiac output (CO). The CO can increase several folds during physical activity but the CaO2 cannot even
be doubled. Thus CO is the main determinant of increased O2 delivery to the tissues during exercise
Concept
Visibly, the person can be seen to have a deeper and higher breathing rate during
exercise. The increased cardiac function is hidden from view. Quite naturally,
since “seeing is believing,” the student is apt to assume that the hyperventilation
is the determining event that ensures the increased oxygen and energy supply to
the tissues.
The lung oxygenation at rest is “perfusion limited.” This term can be quite
confusing and not quite descriptive of what it is meaning to say. This is not to
say that the resting rate of oxygen diffusion across the alveolar-capillary
membrane is inadequate or limited by blood flow.
“Perfusion limited” means that any further increase in lung oxygenation (at
rest, 250 ml/min, the same value as tissue oxygenation or tissue extraction of O2)
can only be possible if the perfusion is not limited, “de-limited” or unlimited by
increasing the pulmonary blood flow.
It is worth reminding that at rest, an equilibrium is achieved between PO2 in
alveolar air and pulmonary blood (103 mmHg) in half the alveolar capillary
transit time. This is the reason for the perfusion-limited characteristic. Further,
an additional transfer of “passenger” oxygen in the lungs is still possible and
easily achieved, if more deoxygenated, mixed venous blood is “driven” to the
“alveolar transit lounge” to pick up and transport more oxygen to the cells.
Then the question is “what is the point of ‘having and catching more breaths’
during physical activity?” The hyperventilation is not without a purpose. The
essential role of increased alveolar ventilation is to maintain the carbon dioxide
partial pressure in the blood. Metabolic CO2 will make the blood acidic,
producing a metabolic acidosis. The respiratory compensation via the
chemoreceptor reflex is the control of the blood pH. The blood pH is reflected
and determined by the concentration ratio of the components of the chemical
buffer system. In the case of the bicarbonate/carbonic acid buffer pH ~
bicarbonate/carbonic acid.
In the lactic acidosis of heavy exercise, the bicarbonate concentration is
reduced. Compensatory hyperventilation will lower the PCO2 to decrease the
carbonic acid component. Blood pH is thus preserved close to physiologic 7.4.
The alveolar ventilation equation relates the arterial blood PCO2 with the
cellular CO2 production (VCO2) and the alveolar ventilation (VA), where
Arterial PCO2 ~ VCO2/VA
Thus, during moderate exercise, the arterial blood PCO2 is relatively
constant. The increased release of metabolic CO2 is matched by the parallel
increase in alveolar ventilation that expels the CO2.
The observant and inquiring student will wonder and question “What then
provides the stimulus for increased alveolar ventilation during exercise if the
major chemical stimulus PCO2 is unchanged?” This question should stimulate
thinking and may cause you to hyperventilate!
8. In reduced hematocrit, how do the partial pressures of oxygen and CO2
change, if any at the pulmonary capillary? Both unchanged oxygenation less,
CaO2 decreased Anemia….no stim of chemo…same as CO poisoning.
Answer
Both the PO2 and the PCO2 of pulmonary capillary blood remain unchanged
since the partial pressures are due to the dissolved fraction of the respiratory
gases.
Concept
The dissolved oxygen in plasma (PO2) determines the percentage of oxygen
saturation of hemoglobin. However, the reverse cause and effect is not true, i.e.,
the amount of oxygen bound to the hemoglobin does not affect the PO2.
Thus, in anemia when the hematocrit is low, the decreased total oxygen that
is bound by hemoglobin does not alter the amount dissolved in solution in
plasma.
Since the PO2 in low hematocirt anemia is unchanged, there will be no
observed aortic/carotid chemoreceptor stimulation of increased breathing in the
patient.
The total oxygen content is, of course, less when the hematocrit is decreased.
The total amount of O2 that diffuses down its partial pressure gradient in the
lungs is higher. But, the diffusion PO2 gradient is unchanged across the alveolarcapillary membrane (103 and 40 mmHg at entry point, respectively).
In carbon monoxide toxicity, the CO competes with its > 200 times higher
affinity for hemoglobin than as for Hb–O2. The blood oxygen content is
drastically reduced by CO competition that wins hands down (or hbO 2 down!).
The dissolved oxygen in plasma, however, is untouched by CO. Therefore, the
chemoreceptors do not sense any decreased PO2 and breathing is not labored or
there is no sign of air hunger.
The person who has CO poisoning will slowly “peter” away and lose
consciousness. This is a common choice method to take one’s life as it can be
unfortunately ended quite “comfortably.”
Would the reduced hematocrit affect CO2 since red cells are essential for
converting metabolic CO2 from the tissues to plasma bicarbonate? This
conversion is catalyzed by the red cell enzyme, carbonic anhydrase (C@). Since
this is a catalytic event, the decrease in hematocrit should not cause any
measurable reduction in the conversion of CO2 to bicarbonate. The mixed
venous blood partial pressure of CO2 should still be 46 mmHg. In the different
case when the C@ enzyme is inhibited, the venous PCO2 can rise.
9. Why is the right heart failure an occurrence in long-term ascend to high
altitude?
Answer
Right ventricular hypertrophy develops due to the pulmonary hypertension that
is caused by general hypoxic pulmonary vasoconstriction.
Concept
The afterload for the left ventricle is the mean aortic or arterial pressure. The
afterload for the right ventricle is the pulmonary arterial pressure. The afterload
represents the pressure against which the ventricles have to pump or generate
sufficient pressure for ejection of stroke volume.
Hypoxic pulmonary vasoconstriction (hpv) is a unique vascular design that
serves the function in optimizing V/Q matching. Should there be a local regional
mismatch of V/Q where the alveoli are underventilated, the decreased alveolar
PO2 will produce the hpv so that the pulmonary blood flow is not “wasted” on
the underventilated alveoli but channeled to well-ventilated alveoli.
This adaptation to regional lung hypoxia at sea level presents a problem
This adaptation to regional lung hypoxia at sea level presents a problem
when the person is exposed for a long time to lower atmospheric oxygen at high
altitudes. The hypoxia is now a general condition throughout the lungs. Thus, we
can expect that the hpv is no longer restricted to a certain area but widespread at
every alveolus.
The cells can be deprived of sufficient oxygen (hypoxia) in various ways. In hypoxic hypoxia, the partial
pressure of O2 (PO2) in blood is reduced. In anemic hypoxia, the hemoglobin-bound and thus the total O2
content is decreased with no change in the PO2. If the cells are metabolically suppressed, the venous blood
PO2 is characteristically elevated
The general increased pulmonary vasoconstriction will raise the pulmonary
arterial pressure.
The right ventricle will, with time, hypertrophy, in response to the increased
cardiac work against the elevated afterload. This early compensation of the
cardiac myocardium may not be adequately sustained in the longer period. The
right ventricle may begin to weaken under the constant need to generate a
greater ventricular tension to maintain a normal cardiac output to the lungs.
The right ventricle can eventually decompensate with resulting pump failure.
10. What compensatory changes in red blood cells (RBC) help to improve
oxygen delivery to the tissues in low atmospheric environment? Number, 2,3
dpg….extreme altitude alkalosis incr affinity.
Answer
The glycolytic metabolite, 2, 3 diphosphoglycerate (DPG) in the red cells
increases and the hemoglobin–oxygen affinity is reduced to promote more
unloading of oxygen to the cells.
Concept
Concept
The cardiorespiratory functions are directed at the final cell consumer. The
physiology is “cell-centered” (I suppose “self-centered!”). Adaptations in
physiology is aimed at ensuring that the functioning unit of physical life, the cell
is nourished adequately for health and physical activity. The neuron and the
cardiomyocyte are the two most essential cell types that are the focus of
physiological, homeostatic attention.
Under hypoxic conditions, the intracellular red cell DPG concentration
increases. DPG decreases the affinity of hemoglobin for oxygen. The main effect
is to increase more unloading of oxygen to the cells.
It might be thought that the upload of oxygen in the lungs will be less with
the reduced Hb–O2 affinity. However, because of the unique sigmoid,
cooperative Hb–O2 interactions, even a drop of arterial PO2 at 60 mmHg will
only reduce the Hb–O2 saturation, just a few percentage to 90 %.
At extreme altitudes, when the atmospheric PO2 becomes critically low for
survival, an increased Hb–O2 affinity effect might be a needed compensation.
This is caused by the respiratory alkalosis from hyperventilation at the high
place.
Alkalosis shifts the oxy–hemoglobin curve to the left with increased Hb–O2
affinity. DPG has the opposite action in a rightward shift of the Hb–O2 curve. At
extreme heights, the alkalotic effect to increase uptake of oxygen in the lungs
takes precedence when the alveolar air PO2 falls too much.
© Springer International Publishing Switzerland 2015
Hwee Ming Cheng, Physiology Question-Based Learning, DOI 10.1007/978-3-319-12790-3_17
17. Cardiorenal Physiology
Hwee Ming Cheng1
(1) Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
Hwee Ming Cheng Email: chenghm@ummc.edu.my
The heart and the kidneys are intimate partners in handling pressure—arterial
blood pressure. The cardiac muscle and renal nephrons both receive sympathetic
nerve inputs which serve as part of the integrative, wired connections between
them. The kidneys also secrete hormones, renin, and erythropoietin which are
“wireless” hormonal signals that maintain the blood volume. Arterial
baroreceptors that monitor blood pressure/volume are found in the carotid
artery/aorta and the preglomerular renal arteriole. There are homeostatic linkages
between sodium balance, blood volume, blood pressure, and urinary excretion of
sodium. Regulated renal tubular secretion of potassium and excretion in the
urine (“pee”) is essential to maintain normal cardiac pacemaker activity. The
three Ps here (pee, potassium, pacemaker) are bound together for life.
1. Which determinant of arterial blood pressure equation is affected by renal
handling of sodium?
Answer
The cardiac output determinant of blood pressure is dependent on blood volume
which in turn changes with the sodium balance (total body sodium).
Concept
The two determinants of blood pressure are total peripheral resistance (TPR) and
cardiac output. Total body sodium is the main determinant of extracellular fluid
(ECF) volume/blood volume. Blood volume changes will affect the mean
systemic filling pressure and hence the venous return.
Sodium balance changes alter the blood volume because sodium is the main
Sodium balance changes alter the blood volume because sodium is the main
determinant of ECF osmolarity. For example, if a person goes on a high sodium
diet, the ECF osmolarity soon changes. Osmoregulation is a rapid physiological
response mechanism involving the hypothalamic osmoreceptors/antidiuretic
hormone (ADH) and the hypothalamic thirst neurons.
The normalization of ECF osmolarity due to the positive sodium balance
leads to new equilibrium of an increased ECF/blood volume.
Eventually the body will activate compensatory mechanisms for the
hypervolemia/positive sodium balance to restore blood volume.
In the renal medulla, water that is reabsorbed from the descending loop of Henle (LoH), the descending
peritubular capillary, vasa recta, and the collecting ducts (under ADH action) are all returned to the
circulation via the ascending vasa recta. There is no dilution or disturbance to the hyperosmotically
stratified medullary interstitium
2. How do the Starling’s forces at the peritubular capillary serve its function?
Answer
The balance of Starling’s forces at the peritubular capillary favors reabsorption
along the length of the peritubular capillary.
Concept
Renal handling includes filtration, reabsorption and secretion. The latter two
tubular processes involve the peritubular capillary. Reabsorption of water and
solutes is the movement across the epithelial cell, transcellularly and/or
paracellularly from the tubular fluid in the lumen into the peritubular capillary.
The peritubular hydrostatic pressure is relatively low due to the high vascular
resistance of the postglomerular efferent arteriole. The glomerular hydrostatic
pressure is high at ~ 50 mmHg and drops to less than 20+ mmHg in the
peritubular capillary.
In contrast, the plasma oncotic pressure in the peritubular capillary is high at
~ 40 mmHg. The end-glomerular blood has an elevated oncotic pressure
(> 35 mmHg) due to high filtration fraction (20 %). The blood that exits the
efferent arteriole enters the peritubular capillary. Therefore, the peritubular
capillary plasma oncotic pressure is greater than its hydrostatic pressure. The net
Starling’s force will be a reabsorptive force.
This is a favorable physiologic situation as a large portion of filtered solute is
reabsorbed at the proximal tubule. An equally high fraction of filtered water
(~ 75 %) is then reabsorbed following the solute reabsorption by isoosmotic
water reabsorption.
Water reabsorption at the kidneys and the intestines are driven by the osmotic gradient. The osmotic
pressure gradient is generated by prior solute transepithelial movement from the lumen to the interstitium.
Water is reabsorbed also at the intestines as the large fluid volume in all the GI secretions (saliva, stomach,
pancreas) has to be recovered. Water moves both transcellularly and paracellularly at the kidneys and the
gut
3. How does a baroreflex affect renal handling of sodium?
Answer
A baroreflex induced sympathetic discharge will increase renal sympathetic
akction to effect decreased sodium urinary excretion.
Concept
Increases in sympathetic nerve action tend to increase cardiac function and
vascular resistance. These combine to raise arterial blood pressure.
Hypotension or hypovolemia will trigger the baroreflex to increase general
sympathetic discharge. Among this increased effector neural action is the renal
sympathetic discharge. Among this increased effector neural action is the renal
sympathetic nerve. Physiologically renal sympathetic action will, in concert also,
help to raise the blood pressure.
The positive effect on blood pressure by renal sympathetic activity acts via
the conservation of sodium. Sodium-dependent blood volume mechanism
provides the link to the regulation of blood pressure.
There are a variety of pathways that renal sympathetic action conserves
sodium. One is by reducing the filtered sodium load since the glomerular
filtration rate (GFR) is decreases by sympathetic constriction of the renal
arterioles. The sympathetic nerve fibers also innervate the proximal tubular cells
and they have a direct effect in increasing sodium reabsorption.
Thirdly, the juxtaglomerular (JG) cells that secrete the hormone/enzyme
renin is stimulated by sympathetic input. Activation of the renin-angiotensin
system increased the plasma concentration of aldosterone, the key hormone that
increases sodium reabsorption at the collecting ducts in the kidneys.
The intrarenal baroreceptors at the afferent arteriole also participate in
compensation during decreases renal blood perfusion when the blood pressure
decreases. However this is not via a neural baroreflex involving the brain stem.
Intrarenal baroreceptors sense directly a reduced renal arterial blood pressure,
and this leads to the increased release of renin from JG cells of the afferent
arteriole into the blood.
4. What vascular action of renal sympathetic contributes to blood pressure
control? Tpr
Answer
The vasoconstriction of the renal arterioles contribute to the TPR. TPR is a
determinant of arterial blood pressure.
Concept
The word “total” in TPR is misleading. It does not imply all regional resistances
to blood flow is changes, either increased or decreased at the same time. When
the sympathetic discharge is increased during a baroreflex, the overall (better
word than “total”) peripheral resistance is increased. This occurs due to
vasoconstriction by the sympathetic nerve to arterioles. However, this
vasoconstricting effect is selective and the increased vascular resistance is
tailored towards organs like the kidneys, gastrointestinal tract and the skin.
It will be noted that these organs are nonessential when we consider the
critical importance of the cerebral and coronary circulations. Increased
sympathetic action arising from baroreceptor activation does not raise the
cerebral and coronary vascular resistance, for obvious reasons if the body is
cerebral and coronary vascular resistance, for obvious reasons if the body is
designed to keep us alive!
The renal sympathetic nerve vasoconstricts both the afferent and efferent
arterioles. This is part of the “selective” vasoconstriction throughout the body to
increase the “overall” peripheral resistance.
The segmented approach in teaching physiology is partly responsible for
why our students commonly do not include the renal sympathetic nerve in TPR
changes. The baroreflex is detailed during the cardiovascular system and
frequently, the sympathetic efferent compensatory actions are described as
actions on cardiac function, venoconstriction/venous return and “total”
peripheral resistance (PR).
Seldom at this point is the renal arterioles stated and when renal arterioles
are mentioned a few weeks later in the curriculum, the focus is generally on the
renal arteriolar resistances and glomerular filtration.
Our teaching of physiology should be rightly “total” and integrated and not
“selective” and compartmentalized.
5. How is the flow autoregulation in coronary and renal circulation effected by
different mechanisms?
Answer
Blood flow autoregulation to the heart is effected by myogenic and metabolic
mechanisms and in the kidneys are mediated by myogenic and the macula densa
(McD) tubule-glomerular feedback.
Concept
Certain organs in the body exhibit intrinsic abilities to autoregulate its blood
flow and are able to maintain a relatively constant flow within a defined range of
blood pressure fluctuations. Hemodynamically, if the perfusion pressure
changes, there will be a parallel change in the blood flow if the vascular
resistance is not altered.
For the heart and the kidneys (and also the brain), this autoregulation is
distinct and independent of extrinsic nerve or hormonal actions.
In these three organs, the smooth muscle of their arterioles demonstrates a
myogenic property of responding to mechanical stretch. An increased stretch by
pressure will produce a myogenic contraction of the blood vessel. This means
that when the perfusion pressure increases, there will be a corresponding
increase in the myogenic contraction. Since the flow is equal to
pressure/resistance, the blood flow is autoregulated to a constant value.
In the coronary circulation, a metabolic feedback could also contribute to the
autoregulation. For example, an acute decrease in perfusion pressure will reduce
autoregulation. For example, an acute decrease in perfusion pressure will reduce
blood flow initially and this will lead to accumulation of metabolites in the
myocardium. Several vasodilator metabolites will then act on the coronary
arterioles and decrease the vascular resistance. This metabolic action cause by
the initial decrease in perfusing pressure will ensure a normal coronary blood
flow.
In the kidneys, a major intrinsic mechanism that autoregulates renal blood
flow (RBF) is tied to its physiologic purpose of autoregulating the GFR. The
structural complex involved in renal autoregulation (RenAg) is the
juxtaglomerular apparatus (JGA). The JGA has two components, the
preglomerular afferent arteriole and the distal tubular McD. In an indirect way,
the McD senses changes in distal tubular fluid electrolyte when the RBF/GFR
changes consequently on renal arterial pressure fluctuations. An initial increase
in renal perfusion pressure will bring more electrolytes that are sensed by the
McD (mainly chloride and sodium ions). The McD is excited and release a
paracrine vasoconstrictor. This local vasoconstrictor diffuses to the
neighborhood afferent arteriole and constricts the blood vessel. The increased
renal perfusion pressure is thus balanced by a higher afferent vascular resistance.
The RBF/GFR is normalized. This intrinsic RenAg mechanism (independent of
the renal sympathetic nerve or circulating hormones) is a feedback from the
distal tubular McD to the preglomerular afferent arteriole, hence, the name
“tubular-glomerular feedback” or simply the McD sensing mechanism.
6. State with brief reasons if RenAG serves primarily a metabolic function?
Answer
The maintenance of RBF and GFR are primarily for handling changes in ECF
volume and electrolyte balance, in particular sodium and potassium. A decrease
in RBF/GFR also has significant effects on secretion and excretion of metabolic
products.
Blood volume sensing is related to monitoring ECF volume changes as the blood volume is a part of ECF.
In the high-pressure arterial side, the carotid and aortic sinus pressure/baroreceptors monitor the blood
volume/pressure. Volume receptors are found in the low-pressure part of the cardiovascular system at the
great veins/right atrium and the pulmonary vasculature. The intrarenal baroreceptors at the preglomerular,
afferent arteriole sense renal arterial pressure
Concept
The essential organs, heart and the brain are critically dependent on an adequate
blood supply for its functions. The RBF obviously also provide energy source,
nutrients and oxygen to the renal tissues. In contrast to the myocardium and the
brain tissues, a major role of RBF (resting 20 % of cardiac output) is to ensure a
normal GFR. A large portion of the oxygen consumption of the kidneys is in the
active reabsorption of sodium and sodium linked solutes.
Fluctuations in GFR will result in parallel fluctuations in filtered load of the
solutes and water. Filtered load is calculated by the product of GFR and the
filtered solute concentration (which is the same as plasma concentration if the
solute is freely filtered). An acute increase of GFR will present a higher load of
tubular fluid to the distal nephrons which may exceed the membrane transport
capabilities further downstream along the nephron.
The importance of an optimal tubular fluid delivery to the distal nephrons is
highlighted by another intrinsic phenomenon besides the McD autoregulatory
mechanism. RenAG of RBF/GFR is not perfect and some fluctuations do occur.
A second event involving the proximal tubule will compensate for changes in the
filtered load that enters the Bowman’s capsule. This is called the glomerulotubular (G-t) balance (sounds like the tubular-glomerular feedback, but this G-t
balance takes place at the proximal tubule.
An increased filtered load of solutes and water will be compensated by an
increase in proximal tubular reabsorption. Similarly, a reduced filtered load will
be accompanied by a decreased reabsorption of fluid and solutes at the proximal
tubule. The G-t mechanism involves changes to peritubular capillary fluid
dynamics involving changes in pericapillary Starling’s forces. Changes in GFR
will affect the hydrostatic and oncotic pressures in the peritubular capillary
“downstream” from the glomerular capillary which is in series with it, connected
by the efferent arteriole.
7. How does a poor cardiac output lead to increased sodium retention by the
kidneys?
Answer
Decreased perfusion of the kidneys is sensed, and this triggers an increased
conservation of sodium in an effort to normalize “perceived hypovolemia” that
conservation of sodium in an effort to normalize “perceived hypovolemia” that
causes the poor RBF.
Concept
The kidneys are hard wired to ensure that the heart pumps a normal cardiac
output. The communication “bloody” line between the heart and the kidneys is
the blood pressure. A reduced cardiac output is insufficient to sustain an arterial
blood pressure that is needed to circulate blood to the peripheral organs.
The kidneys detect this hypotension at the intrarenal baroreceptors at the
afferent renal arteriole. The kidneys “perceive” any reduced perfusion pressure
as possibly resulting from hypovolemia. As such, the renal mechanisms
activated during poor cardiac output (although blood volume is normal) act to
increase sodium and water retention.
Sensing of hypotension by the renal baroreceptors will release renin. The
sequential progression of the renin-angiotensin pathway produce the bioactive
angiotensin II. Angiotensin II is a primary stimulus of aldosterone secretion from
the adrenal cortex. The angiotensin II (AII) and aldosterone both act to increase
renal tubular sodium reabsorption.
AII also directly promote sodium reabsorption at the proximal tubule.
Sodium retention is also contributed by a reduced load of sodium filtered. This is
due to vasoconstriction of renal arterioles by AII. The AII vasoconstricts the
renal arterioles and besides lowering sodium filtered load, this renal
vasoconstriction also sums up with other regional resistances into the TPR.
A reduced cardiac output will activate the carotid/aortic baroreceptors. The
effector sympathetic discharge from a baroreflex has identical actions as AII in
decreasing filtered sodium load, increase TPR and stimulate proximal tubular
sodium reabsorption. Renal sympathetic nerve action also stimulates renin
secretion which has the end effect of decreasing urinary sodium excretion.
8. When you drink a large volume of water in a few minutes, does your kidney
regulate blood osmolarity, blood volume or both? Give your rationale.
Answer
Consuming a large volume of water leads to positive water balance. This is
rapidly adjusted by an increased excretion of hypotonic urine via inhibition of
osmoreceptor/ADH mechanism.
Concept
Should the ECF volume change, the student must ask whether there is also any
change in the sodium balance (total body sodium). This is because the control of
sodium balance (related to ECF volume) by the renin-angiotensin mechanism
sodium balance (related to ECF volume) by the renin-angiotensin mechanism
(RAS), renal sympathetic nerve action does not need to participate
physiologically if the sodium balance is unchanged.
This is the scenario in the hypotonic expansion from drinking water.
Although the volume of the ECF has increased, it will be incorrect to state, e.g.,
that a compensatory inhibition of the RAS by the increases ECF/blood volume
will be part of the compensation. This is merely a positive water balance with no
change in the sodium balance. It is often mistaken when the parameters “sodium
concentration” and sodium balance are used interchangeably. If RAS inhibition
is involved, then an increased sodium excretion in the urine will follow. This
will not make physiologic sense as the person has a normal sodium balance
before drinking the water. If RAS inhibition occurs, the person will end up with
a negative sodium balance although he drinks only water!
The body can rapidly respond to the positive water balance by
osmoregulation. Osmoregulation of the ECF is rightly linked to controlling the
sodium concentration of the ECF. This is because sodium concentration is the
main determinant of the ECF osmolarity. Drinking an excess volume of water
will lower the sodium concentration/osmolarity of the ECF. This produce
inhibition of the hypothalamic osmoreceptors and the ADH/vasopressin
secretion from the posterior pituitary is inhibited.
The urinary excretion of water increases in positive water balance. The urine
is dilute and large in volume. Note that the urinary sodium excretion
(amount/time) is unchanged, although the sodium concentration in the hypotonic
urine is lower.
The brain and sodium balance. Blood volume changes are monitored, and sensor information processed in
the brain stem. The autonomic sympathetic nerve activity is a major effector in the blood volume/pressure
control. Increased/decreased renal sympathetic actions restore normal sodium balance, which is the main
determinant of ECF/blood volume
9. How does the renal control of electrolyte balance maintain normal cardiac
9. How does the renal control of electrolyte balance maintain normal cardiac
electrical function?
Answer
Perhaps the most important electrolyte regulated by the kidneys which affect
cardiac activity is potassium.
Concept
Renal function is essential for electrolyte balance in the ECF and this includes
sodium, calcium and potassium (also magnesium which we know less of its
established physiology). Sodium balance and volume of ECF/blood are
interrelated and govern by renal mechanisms operating in concert with
cardiovascular control of blood pressure.
Calcium ion is involved in the depolarization of the sinoatrial pacemaker
cells and also in the prolonged depolarization phase of the ventricles.
Hypoclacemia and hypercalcemia do have effects on cardiac function. The
kidneys in combination with the triad of hormones, parathyroid, vitamin D and
calcitonin participate in the homeostasis of calcium.
Clinically, changes in ECF potassium have profound effects on the
myocardium. The resting membrane potential of a cell is due to the
transmembrane potassium concentration gradient. In hypokalemia, cardiac cells
are hyperpolarized and less excitable.
In hyperkalemia, a constant elevated ECF potassium may initially produce
increased excitability of the myocardium. However, the hyperkalemia-induced
partial depolarization will eventually lead to inactivation of the voltage-gated
sodium channels. Critically, the heart can cease to beat.
ECF potassium, at a low regulated level of 4–5 mmol/L is monitored by cells
that secrete aldosterone from the adrenal cortex. Hyperkalemia stimulates
aldosterone release (postprandial hyperkalemia stimulates insulin also).
Aldosterone acts on the principal cells at the collecting ducts to promote tubular
secretion of potassium. Both the basolateral K/Na ATPase and the luminal
membrane potassium channels are increased by aldosterone to enhance
potassium secretion.
The homeostasis of potassium includes this hormonal fine-tuning of tubular
secretion because on a normal daily diet excess potassium is added to the ECF .
The cardiac output is monitored by the kidneys and respiratory function. The peripheral chemoreceptors
(carotid/aortic bodies) can be stimulated in stagnant hypoxia. Decreased effective circulatory volume is
sensed by the intrarenal baroreceptors at the afferent arteriole. This is the physiologic “Reno-Respi CO
Sandwich”
10. How does proteinuria change the capillary fluid dynamics in skeletal
muscle?
Answer
Proteinuria decreases the plasma oncotic pressure and this tends to increase the
net filtration at the capillary predisposing to edema.
Concept
Traditionally, the explanation for peripheral edema due to proteinuria is
described as follows: Loss of protein in the urine reduced the plasma oncotic
pressure that is the key reabsorptive osmotic force at the capillary. The balance
of Starling’s forces favors a greater filtration at the arteriolar end of the capillary.
At the venular end of the capillary, the recovery or reabsorption of fluid from the
interstitial space into the capillary is also decreased. Fluid, thus, accumulates in
the interstitial compartment of the ECF.
The corresponding contraction of the vascular blood compartment is also
viewed as a stimulus that then activates the volume-conservating reninangiotensin system. This accounts for the sodium and fluid retention in the
person.
Recently, alternative proposals for the link between proteinuria and
development of peripheral edema have been raised.
© Springer International Publishing Switzerland 2015
Hwee Ming Cheng, Physiology Question-Based Learning, DOI 10.1007/978-3-319-12790-3_18
18. Respi-Renal Physiology
Hwee Ming Cheng1
(1) Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
Hwee Ming Cheng Email: chenghm@ummc.edu.my
The lungs take in air and let out air. The kidneys take in fluid and let out fluid.
The oxygenated blood from the lungs is circulated to the kidneys. The carbon
dioxide in the arterial blood has a physiologic role in modifying the renal tubular
handling of bicarbonate and hydrogen ions. The lungs and the kidneys are major
players in the daily military physio-drama of pH defence. The combined
respiratory and renal strategies victoriously prevent any pH disturbance and
maintain a stable optimal pH of the extracellular fluid (ECF).
Besides critical roles in pH regulation, the kidneys and the lungs release
hormones that participate centrally in the control of arterial blood pressure. The
cardiovascular system joins them in this physiologic triumvirate to ensure a
constant perfusion pressure from the heart to all cells in the body.
ECF/Blood pH is carefully regulated by chemical buffers that are integrated with respiratory and renal
functions. The major daily acid load is carbonic acid and the lungs remove the excess metabolic CO2.
Noncarbonic acids are handled by the renal nephrons that secrete hydrogen ions and restore blood
bicarbonate, the major base in the ECF
1. Do the lungs or the kidneys excrete most of the daily acid load?
Answer
The lungs eliminate most of the daily acid production which is carbonic acid
from metabolism of foods.
Concept
The daily production of acid is about 15 moles. A large portion of this daily acid
load is carbonic acid from the hydration of metabolic CO2. Normal respiratory
function is thus essential to maintain the arterial blood pH of 7.4. A pH of 7.4 is
equivalent to a hydrogen ion concentration of 40 nmol/L (1 nmol = 10−9 mol).
For noncarbonic acids produced from metabolism, the kidneys are the only
route for excretion. The daily renal excretion of acid is much less at about
70 mmole. One millimole is still 1 million times the concentration of 1 nmol!
Therefore, the renal function is critical for preservation of normal body fluid pH.
The time line for respiratory control of pH is earlier than that for renal
excretion of acid. However, although renal compensations for pH fluctuations
takes a longer time, the renal handling of acid and recovery of the main base,
bicarbonate ion effectively rectifies and restores the ECF pH in response to any
acid–base challenges.
The pH of ECF is reflected and associated with the respective ratios of the base/acid pairs of all the
chemical buffers. Quantitatively, the major ECF buffer is the bicarbonate/carbonic acid system. Renal
function targets the bicarbonate component while respiratory function, via regulating PCO2 affects the
carbonic acid
2. How does a renal hormone compensate in two ways in pulmonary
hypoventilatory conditions?
hypoventilatory conditions?
Answer
The kidneys will secrete erythropoietin. The respiratory acidosis will also
increase tubular acid secretion.
Concept
In hypoventilation, the partial pressure of O2 in arterial blood will decrease. The
hypoxia will be detected by the kidneys and the renal hormone erythropoietin
will be secreted. Erythropoietin will increase red cell production and a secondary
polycythemia will develop.
This hypoxia-induced compensation in a higher hematocrit is also seen in
during acclimatization to high altitude hypoxia. A large polycythemic
compensation is counterproductive, however, as the increased hematocrit will
increase the blood viscosity. Vascular resistance to blood flow will then be
higher.
In addition, the kidneys will respond to the respiratory acidosis by increasing
tubular hydrogen secretion. The secretion of more H+ by the renal tubules is
linked to replenishing the blood bicarbonate concentration. Both reabsorption
and new synthesis of bicarbonate by the tubules is increased when the H+
secretion is higher.
There is evidence that changes in ECF pH also affect some other hormones
that act on the renal tubular secretion of H+. Acidosis stimulates renal renin
secretion. The generation of angiotensin II (AII) along the activated reninangiotensin pathway helps to increase the blood pH. AII stimulates a hydrogen
ATPase transporter in the collecting ducts. Hydrogen ions are also secreted when
AII acts on the sodium hydrogen countertransporter at the proximal tubule.
Acidosis also stimulates the release of the adrenal steroid hormone
aldosterone. Aldosterone stimulates a hydrogen ATPase to increase acid
secretion by the nephrons.
The renal tubules secrete hydrogen ions. The tubular intracellular biochemistry that produces the protons is
linked to the tubular reabsorption of filtered bicarbonate and also the synthesis of new bicarbonate to
replace ECF bicarbonate ions that have been consumed during chemical buffering
3. How does arterial blood PCO2 affect the renal tubular acid secretion?
Answer
Increased arterial PCO2 will increase tubular secretion of hydrogen ions in the
kidneys.
Concept
The renal tubular cells at the proximal tubule and at the collecting ducts secrete
H+.
The two main stimuli which affect tubular acid secretion is blood PCO2 and
blood pH. If PCO2 is increased or pH is decreased, the renal tubules will secrete
more H+.
For CO2, this is more easily visualized. CO2 from the peritubular capillary
enters the tubular cells at the basolateral side and is hydrated to carbonic acid by
carbonic anhydrase (C@). The carbonic acid then dissociates into bicarbonate
ions and H+. The proton is secreted at the lumial membrane into the lumen.
For a low pH, the cell signaling mechanism is less obvious. We can envisage
pH sensors on the basolateral membrane of the tubular epithelial cells. Detection
of a reduced ECF pH by the basolateral border will then lead to increased
cellular machinery to secrete more acid. These cellular effects of the low
interstitial pH could include upregulating C@ activity and the appearance of
more luminal sodium–H+ exchange transporters.
The major ECF chemical buffer is the bicarbonate/PCO2 buffer system.
Quantitatively, this is the most efficient buffer as it is an “open” system. The
“openness” of the system means that both the numerator bicarbonate and the
denominator PCO2 are linked to the renal function and pulmonary function
respectively. This is sometimes written nicely as
A respiratory acid base disturbance will thus be compensated by renal
tubular reactions. A respiratory acidosis during alveolar hypoventilation will
lead to reduced renal secretion of acid. This also means that the tubular
reabsorption and synthesis of HCO3 is decreased. Similarly, if the acid–base
fluctuation is due to a renal cause, respiratory adjustments will take place. If the
pH disturbance is due to a nonrespiratory, nonrenal reason, then both the lungs
and the kidneys can compensate, e.g., metabolic acidosis from diarrhea.
The total excreted hydrogen ions in urine is predominantly bound to urinary buffers, mainly phosphate and
as ammonium ions. The measured urinary pH is due only to the free, unbound H+. At the urinary pH of 4.4,
this is still a small amount of H+ (1000 × 40 nmol/L or 40 μmol/L of urine)
4. During vomiting, does the renal function compensate effectively?
Answer
Vomiting leads to a metabolic alkalosis which is not effectively compensated by
the kidneys due to contraction alkalosis.
Concept
The loss of gastric acid during vomiting results in a metabolic alkalosis. The
respiratory compensation will be a decreased alveolar ventilation due to a
depressed stimulation of the arterial chemoreceptors.
The kidneys would be expected to reduce its tubular secretion of acid,
produce an alkaline urine to compensate for the metabolic alkalosis. However,
produce an alkaline urine to compensate for the metabolic alkalosis. However,
there is a paradoxical acidic urine in the metabolic alkalosis resulting from the
loss of gastric acid.
This is due to the activation of the renin angiotensin system (RAS) by
hypovolemia due to fluid loss in the vomitus. Two components of the RAS
stimulate tubular secretion of H+. This phenomenon of a hypovolemia-driven
alkalosis is called “contraction alkalosis.”
Fluid replacement in the sick person will restore the normal effectiveness of
the kidneys to adjust to the alkalosis.
The increased blood pH will reduce the proton secretion, which is also
accompanied by less tubular reabsorption and synthesis of bicarbonate.
Note that the respiratory reflex should increase the PCO2. How then does this
elevated PCO2 not oppose the appropriate tubular response to metabolic
alkalosis to secrete less acid? In metabolic alkalosis, the filtered load of
bicarbonate is still high enough that an excess of bicarbonate still escapes
reabsorption. In addition, if the alkalosis is severe, secretion of bicarbonate can
also occur at specific intercalated cells at the collecting ducts.
5. Compare the functions of carbonic anhydrase in the respiratory and renal
physiology.
Answer
In red blood cells, the enzyme carbonic anhydrase is essential for the formation
of bicarbonate, the major form of CO2 transported in blood. In renal tubules,
carbonic anhydrase is need for three processes, namely the reabsorption and
synthesis of bicarbonate plus the secretion of hydrogen ions.
Concept
The enzyme, carbonic anhydrase, C@ is the key catalyst in the hydration
reaction of carbon dioxide. The C@ is minimum in the plasma and found in the
cytoplasm of erythrocytes. CO2 enters the red cells and is hydrated to carbonic
acid, which dissociates to bicarbonate and proton. The bicarbonate exits the red
cells in exchange with chloride while the H+ is buffered by hemoglobin.
In renal tubules, the C@ is found both inside the cells and also on the cell
membranes. Specifically, this is the enzymatic scenario at the proximal tubule.
The C@ at the luminal membrane catalysed the reaction between secreted H +
and filtered HCO3. The reaction in the lumen proceeds to CO2 and water. The
CO2 enters the proximal tubular cell is rehydrated by cytosolic C@. Inside the
proximal epithelial cells, both bicarbonate and proton is generated. The proton is
then secreted via the sodium/hydrogen antiporter into the tubular fluid. The
HCO3 also leaves the cell but at the basolateral membrane and is reabsorbed into
the peritubular capillary. Note that the filtered bicarbonate is reabsorbed not
directly at the luminal surface but by a “convoluted” indirect pathway as
described.
The carbon dioxide can also enter cells at the basolateral side. This is the
situation when we consider the tubular synthesis of new bicarbonate. Note that at
the proximal tubular reaction above, the filtered bicarbonate is merely
reabsorbed and there is no synthesis of new bicarbonate (the proximal
ammonium synthesis does produce HCO3). Also, the secreted H+ at the proximal
tubule does not become excreted in urine but is incorporated as water to be
reabsorbed. The C@ catalysed pathway inside tubular cells of the collecting
ducts is involved in both the tubular secretion of H+ for the urinary excretion of
ammonium and titratable acids, mainly urinary phosphate.
Interestingly, the gastric parietal cells that secrete hydrogen ions also uses
the same C@. In parietal cells, CO2 is hydrated and dissociated to produce H+
and bicarbonate. The hydrogen is secreted into the gastric lumen as part of
hydrochloric acid in gastric juice. The HCO3, however, exits the parietal cell at
the basolateral membrane. This accounts for the postprandial increase in blood
pH also called “alkaline tide”.
CO2 is not merely a metabolic waste. CO2 is the principal chemoregulator of normal breathing. Carbonic
acid is a component of the major extracellular fluid bicarbonate/carbonic acid buffer. Tissue CO2 is a key
arteriolar vasodilator that effects cerebral and coronary blood flow autoregulation, and also regional tissue
active and reactive hyperemia
6. How do the kidneys alter urine composition to help to ascend mountains?
Answer
The urine becomes alkaline with more excretion of bicarbonate. This resensitizes
the central chemoreceptors that were inhibited by the high altitude, hypoxiainduced respiratory alkalosis.
Concept
Carbon dioxide is the dominant chemical regulator for respiration. During an
ascent to high altitude, hypoxia is the primary stimulus for increased ventilation.
The increased breathing soon produces a respiratory alkalosis due to more CO2
being removed. The hypoxic hyperventilatory response is thus opposed by the
hypocapnia.
Acclimatization towards a better ventilatory response takes place over the
next few days. The hypocapnia raise the pH of the interstitial fluid that surround
the chemoreceptors in the brain stem.
The sensitivity of the chemoreceptors is improved when this pH is decreased.
This is effected by urinary excretion of bicarbonate. The decreased partial
pressure of CO2 will cause the renal tubular cells to decrease bicarbonate
reabsorption.
Mountain climbers can speed up the acclimatization process by taking
carbonic anhydrase inhibitor. The reabsorption of filtered HCO3 at the proximal
tubule is dependent on carbonic anhydrase (C@), present at both the luminal
membrane and inside the tubular cells. Inhibition of C@ will lead to an
increased renal clearance of bicarbonate in the urine. This is renal compensation
for respiratory alkalosis.
A minor expected effect would be a slight increase in acidity of the venous
blood. This is because the red cell C@-catalysed production of bicarbonate will
be suppressed.
7. Compare the effects of sympathetic activity on airflow and renal blood flow?
Answer
The sympathetic nerve acts to produce bronchodilation and vasoconstrict the
renal arterioles.
Concept
The effect of autonomic sympathetic nerve action on bronchial smooth muscle is
mainly indirect via stimulating the secretion of adrenal caecholamines,
adrenaline/noradrenaline. Adrenaline acts on the same beta adrenergic receptors
adrenaline/noradrenaline. Adrenaline acts on the same beta adrenergic receptors
on airway smooth muscle that is bound by neurotrans mitter noradrenaline
releases from postganglionic sympathetic fibers. An airway resistance is
decreased with bronchodilation. This effect makes sense when we think of the
general increase in sympathetic activity during exercise when breathing rate is
increased.
The effect or renal sympathetic nerve on renal arteriolar smooth muscle is to
produce vasoconstriction. Renal blood flow and hence glomerular filtration rate
(GFR) is decreased. If we think of the exercise scenario again, the increased
sympathetic arteriolar constriction has a role is redistributing the cardiac output
to the skeletal muscles where metabolism is higher. The renal vasoconstriction is
an alpha adrenergic receptor binding effect.
The renal arteriolar constriction also has a function in maintaining arterial
blood pressure by affecting the “total” peripheral resistance (TPR). The blood
vessels are dilated in the exercising skeletal muscles, and this reduces the TPR.
The blood pressure is still maintained by a greater cardiac output and selective
vasoconstriction in organs including the renal and splanchnic vasculature.
The mesangial cells at the glomerular region are smooth muscle-type cells
and they respond to vasoactive agents. Mesangial cell contraction will decrease
the total area available for filtration and lower the GFR.
Renal sympathetic action in the kidneys has a key role in conserving sodium.
These effects on sodium balance in turn regulate ECF/blood volume and operate
via a reduction in filtered load of sodium and stimulating secretion of renin and
its antinatiruretic hormones in the renin-angiotensin system.
8. State the effect, if any of hypoxia on pulmonary and renal vasculature.
Answer
In the lungs, hypoxia causes a unique pulmonary vasoconstriction. The renal
tissues are relatively tolerant to hypoxia.
Concept
In the lungs, the blood vessels do not respond in the usual way as seen in other
tissues. In all other organs, when blood oxygen supply is inadequate to meet
metabolic demand, the tissue hypoxia will compensate by vasodilating the blood
vessels. Hypoxic pulmonary vasoconstriction (HPV) is thus not a response to
ensure sufficient oxygen to the pulmonary alveoli (the lungs are filled with O2rich air; perhaps the bronchial vasculature that supplies nonalveoli structures has
similar hypoxic-vasodilation response).
The physiologic pulmonary rationale for the HPV is to maintain an optimal
The physiologic pulmonary rationale for the HPV is to maintain an optimal
ventilation/perfusion matching at the alveoli exchange area.
The renal blood flow has a major role in providing a normal, large GFR
(180 L/day; note plasma volume is around only 3 L). The tissue oxygen
extraction for the kidneys is mainly used to provide energy for the tubular
transport processes. The key epithelial cell transporter at the basolateral
membrane is the Na/K ATPase. Since a lot of solutes are transported at the
tubules via sodium-linked mechanisms, there is a proportionate relationship
between renal oxygen consumption and the rate of tubular sodium reabsorption.
Hypoxia, of course, increases the renal erythropoietin production and release.
9. How is pulmonary blood flow and renal blood flow determined by using the
same experimental principle?
Answer
Fick’s principle is used for determining pulmonary blood flow, using oxygen as
the measured parameter and for renal blood flow, the solute measured is p-amino
hippuric acid (PAH).
Concept
Fick’s principle is used to estimate regional blood flow. The equation states that
the organ blood flow is equal to the rate of “extraction” of the solute (Es)
divided by the arterial-venous concentration difference (Sa—Sv) of the solute,
i.e.,
For pulmonary blood flow, Es is the rate of oxygenation ml O2/min, and the
oxygen content difference between pulmonary venous/arterial blood is used.
For renal blood flow (RBF), the renal plasma flow is determined and the
RBF calculated from knowing the hematocrit. In addition, the value obtained for
renal plasma flow is underestimated by about 10 % since not all the RBF is
delivered to the glomeruli for filtration.
RBF is estimated by using the renal clearance of PAH.
Es is the extracted (excreted load) of PAH. At a small concentration of PAH
used, the venous PAH concentration is zero as PAH, an organic acid, will all be
secreted by the renal tubules. Thus, the flow formula is simplified to excreted
load of PAH/arterial PAH concentration. This converts actually to the renal
clearance of PAH.
10. Is respirator disturbance of acid–base balance associated with any pH
associated flux of potassium across the renal tubular membranes?
associated flux of potassium across the renal tubular membranes?
Answer
Respiratory causes of acid–base imbalance generally do not produce any
transmembrane potassium shift since the primary disturbance is in CO2.
Concept
Carbon dioxide is lipid-soluble and moves freely across cell membranes.
Therefore, there is no need for K+ exchange across the membranes to preserve
electroneutrality.
This noninvolvement of potassium shift is also seen in several forms of
metabolic acidosis. In lactic acidosis, the lactate is available to enter the cell with
the hydrogen ion, and electroneutrality is preserved.
If hydrogen ions enter the cells, and this is not accompanied by any anion,
then the intracellular potassium cations efflux to maintain electroneutrality.
Thus, in this situation, acidosis or academia produces a secondary hyperkalemia.
At the renal tubular epithelial cells, this efflux of K+ into the peritubular
capillary also means that the secretion of K+ into the tubular fluid is less. The
“efflux” may in reality be due to an inhibition of Na/K ATPase by acidosis
which will reduce the pumping of K+ into cells.
In metabolic alkalosis, the reverse cation exchange between H+ and K+ can
take place. The intracellular buffers, organic phosphates and proteins can release
H+ which exits the cells. Potassium enters cell and hypokalemia is precipitated
by the alkalosis.
Students who are discerning will note that for potassium to enter cells, it
must move against a steep concentration gradient, at least 30 times higher inside
the cells (ECF 4 mmol/L, intracellular fluid (ICF) 140 mmol/L). This indicates
that the K/H transmembrane exchange is a more complex event and not merely a
function of a definite membrane protein antiporter.
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